bims-medica 2025-02-09 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2025–02–09
33 papers selected by
Brett Chrest, Wake Forest University

Mitochondria-targeting of oxidative phosphorylation inhibitors to alleviate hypoxia and enhance anticancer treatment efficacy.
Lactate homeostasis is maintained through regulation of glycolysis and lipolysis.
The emerging role of dysregulated propionate metabolism and methylmalonic acid in metabolic disease, aging, and cancer.
Fluxomics Combined with Shotgun Proteomics Reveals a Differential Response of Bovine Kidney Cells to Extracellular Palmitic and α-Linolenic Acid.
PSTK inhibition activates cGAS-STING, precipitating ferroptotic cell death in leukemic stem cells.
Adherence to the Mediterranean diet and colorectal cancer risk: a large case control study in the Moroccan population.
Alternate-day fasting enhanced weight loss and metabolic benefits over pair-fed calorie restriction in obese mice.
The association between dietary inflammatory potential and risk of total and site-specific colorectal cancer: a systematic review and meta-analysis of observational studies.
Harmful metabolic acidosis in children treated by ketogenic diet during prolonged general anesthesia for epilepsy surgery: A single center experience.
Fueling metabolic disruption via FMD to boost chemotherapy in TNBC.
Multi-dimensional evidence from the UK Biobank shows the impact of diet and macronutrient intake on aging.
Design, Synthesis, and Assessment of Tricarboxylic Acid Cycle Probes.
Optical imaging provides flow-cytometry-like single-cell level analysis of HIF-1α-mediated metabolic changes in radioresistant head and neck squamous carcinoma cells.
Rhodoquinone carries electrons in the mammalian electron transport chain.
Resistance to FLT3 inhibitors involves different molecular mechanisms and reduces new DNA synthesis.
The safety and efficacy of a protein-free diet with ketoacid analogues in chronic kidney disease-affected diabetic rats.
Mitochondrial abnormalities as a target of intervention in acute myeloid leukemia.
The pentose phosphate pathway (PPP) in the glioma metabolism: A potent enhancer of malignancy.
Adaptive Plasticity Tumor Cells Modulate MAPK-Targeting Therapy Response in Colorectal Cancer.
Oxidative Phosphorylation (OXPHOS) Promotes the Formation and Growth of Melanoma Lung and Brain Metastases.
Glutamine deprivation confers immunotherapy resistance by inhibiting IFN-γ signaling in cancer cells.
Dietary Acid Load and Human Health: A Systematic Review and Meta-analysis of Observational Studies.
Causal associations between dietary habits and liver cancer risk: a two-sample Mendelian randomization study.
Impact of Dapagliflozin on Hepatic Lipid Metabolism and a Dynamic Model of Ketone Body Levels.
The mitochondria as an emerging target of self-renewal in T-cell acute lymphoblastic leukemia.
Venetoclax plus Daunorubicin and Cytarabine for Newly Diagnosed Acute Myeloid Leukemia: Results of a Phase 1b Study.
Targeting ceramide transfer protein sensitizes AML to FLT3 inhibitors via a GRP78-ATF6-CHOP axis.
Association between Healthy Eating Index 2015 and metabolic syndrome among US cancer survivors: evidence from NHANES 2005-2016.
Association of dietary intake with cancer of the digestive system: a cross-sectional study.
Metformin in overcoming enzalutamide resistance in castration-resistant prostate cancer.
SLC31A1 promotes chemoresistance through inducing CPT1A-mediated fatty acid oxidation in ER-positive breast cancer.
Pediatric AML: state of the Art and Future Directions.
Omega-3 polyunsaturated fatty acids modify glucose metabolism in THP-1 monocytes.

Clin Cancer Res. 2025 Feb 03.

Mitochondria-targeting of oxidative phosphorylation inhibitors to alleviate hypoxia and enhance anticancer treatment efficacy.

Anne P M Beerkens, Sandra Heskamp, Flavia V Reinema, Gosse J Adema, Paul N Span, Johan Bussink.

Hypoxia is a common feature of solid tumors and is associated with a poor response to anticancer therapies. Hypoxia also induces metabolic changes, such as a switch to glycolysis. This glycolytic switch causes acidification of the tumor microenvironment (TME), thereby attenuating the anticancer immune response. A promising therapeutic strategy to reduce hypoxia and thereby sensitize tumors to irradiation and/or antitumor immune responses is pharmacological inhibition of oxidative phosphorylation (OXPHOS). Several OXPHOS inhibitors (OXPHOSi) have been tested in clinical trials. However, moderate responses and/or substantial toxicity has hampered clinical implementation. OXPHOSi tested in clinical trials inhibit the oxidative metabolism in tumor cells as well as healthy cells. Therefore, new strategies are needed to improve the efficacy of OXPHOSi while minimizing side effects. To enhance the therapeutic window, available OXPHOSi have, for instance, been conjugated to triphenylphosphonium (TPP+) to preferentially target the mitochondria of cancer cells, resulting in increased tumor uptake compared to healthy cells, as cancer cells have a higher mitochondrial membrane potential. However, OXPHOS inhibition also induces reactive oxygen species (ROS), and subsequent antioxidant responses, which may influence the efficacy of therapies, such as platinum-based chemotherapy and radiotherapy. Here, we review the limitations of the clinically tested OXPHOSi metformin, atovaquone, tamoxifen, BAY 87-2243 and IACS-010759 and the potential of mito-targeted OXPHOSi and their influence on ROS production. Furthermore, the effect of the mitochondria-targeting moiety TPP+ on mitochondria is discussed as this affects mitochondrial bioenergetics.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-3296
Cell Metab. 2025 Jan 29. pii: S1550-4131(24)00491-1. [Epub ahead of print]

Lactate homeostasis is maintained through regulation of glycolysis and lipolysis.

Won Dong Lee, Daniel R Weilandt, Lingfan Liang, Michael R MacArthur, Natasha Jaiswal, Olivia Ong, Charlotte G Mann, Qingwei Chu, Craig J Hunter, Rolf-Peter Ryseck, Wenyun Lu, Anna M Oschmann, Alexis J Cowan, Tara A TeSlaa, Caroline R Bartman, Cholsoon Jang, Joseph A Baur, Paul M Titchenell, Joshua D Rabinowitz.

  Lactate is among the highest flux circulating metabolites. It is made by glycolysis and cleared by both tricarboxylic acid (TCA) cycle oxidation and gluconeogenesis. Severe lactate elevations are life-threatening, and modest elevations predict future diabetes. How lactate homeostasis is maintained, however, remains poorly understood. Here, we identify, in mice, homeostatic circuits regulating lactate production and consumption. Insulin induces lactate production by upregulating glycolysis. We find that hyperlactatemia inhibits insulin-induced glycolysis, thereby suppressing excess lactate production. Unexpectedly, insulin also promotes lactate TCA cycle oxidation. The mechanism involves lowering circulating fatty acids, which compete with lactate for mitochondrial oxidation. Similarly, lactate can promote its own consumption by lowering circulating fatty acids via the adipocyte-expressed G-protein-coupled receptor hydroxycarboxylic acid receptor 1 (HCAR1). Quantitative modeling suggests that these mechanisms suffice to produce lactate homeostasis, with robustness to noise and perturbation of individual regulatory mechanisms. Thus, through regulation of glycolysis and lipolysis, lactate homeostasis is maintained.

Keywords:  HCAR1 signaling; TCA cycle; competitive catabolism; diabetes mellitus; insulin resistance; insulin signaling; lactate metabolism; metabolic flux; metabolic homeostasis; quantitative modeling

DOI:  https://doi.org/10.1016/j.cmet.2024.12.009
Cell Metab. 2025 Feb 04. pii: S1550-4131(25)00005-1. [Epub ahead of print]37(2): 316-329

The emerging role of dysregulated propionate metabolism and methylmalonic acid in metabolic disease, aging, and cancer.

Moniquetta Shafer, Vivien Low, Zhongchi Li, John Blenis.

  Propionate metabolism dysregulation has emerged as a source of metabolic health alterations linked to aging, cardiovascular and renal diseases, obesity and diabetes, and cancer. This is supported by several large cohort population studies and recent work revealing its role in cancer progression. Mutations in several enzymes of this metabolic pathway are associated with devastating inborn errors of metabolism, resulting in severe methylmalonic and propionic acidemias. Beyond these rare diseases, however, the broader pathological significance of propionate metabolism and its metabolites has been largely overlooked. Here, we summarize earlier studies and new evidence that the alteration of this pathway and associated metabolites are involved in the development of various metabolic diseases and link aging to cancer progression and metastasis.

Keywords:  BCAA metabolism; BCAAs; MMA; aging; branched-chain amino acids; cancer metabolism; metabolic disorders; methylmalonic acid; methylmalonyl-CoA; propionate; propionyl-CoA

DOI:  https://doi.org/10.1016/j.cmet.2025.01.005
Physiol Genomics. 2025 Feb 07.

Fluxomics Combined with Shotgun Proteomics Reveals a Differential Response of Bovine Kidney Cells to Extracellular Palmitic and α-Linolenic Acid.

Linda M Beckett, Sara Scinto, Emma Shelton, Kyrstin M Gouveia, Chaylen Andolino, Addison M Hill, Nishanth E Sunny, Susan Hilger, Madeline P Sheeley, Juliana Guimarães-Laguna, Dorothy Teegarden, Theresa M Casey, Shawn S Donkin.

  Pyruvate carboxylase (PC) catalyzes the formation of oxaloacetate, a TCA cycle intermediate and gluconeogenic substrate. Altering saturated to unsaturated fatty acid ratio alters PC expression, suggesting a central role in mediating carbon flow through metabolic pathways. Herein, we describe changes in metabolic flux of TCA cycle intermediates and proteome in Madin Darby bovine kidney (MDBK) cells with PC expression knocked-down (PC-KD), overexpressed (PC-OE), unaltered using a Scramble control, or cells pretreated for 21 h with vehicle control bovine serum albumin (BSA) or different ratios of palmitic acid (P) and α-linolenic acid (L) ranging from 1 mM P:0 mM L (1P:0L) to 0P:1L. All cells were collected for proteome analysis and to measure [U-13C] pyruvate flux or oxidation of [1-14C] palmitic acid and [U-14C] lactate. Compared to Scramble, 13C enrichment of all TCA cycle intermediates was greater in PC-OE, but all were reduced in PC-KD except succinate. Proteins greater in abundance in both cell lines included solute transporters, propionyl CoA carboxylase, and fatty acid binding protein 3. Relative to BSA, 1P:0L increased cell death and increased 13C flux to citrate but decreased enrichment of succinate. Abundance of citrate synthase, aconitase, glutamine aminotransferases, and succinyl CoA synthetases was greater in 1P:0L, but not different in other pretreatments. Results indicate preferential utilization of pyruvate and amino acids by 1P:0L cells whereas 0P:1L treated cells show preference for α-linolenic acid metabolism. PC regulates metabolic flux, C18:3n-3 cis prevents lipotoxicity, and both alterations in PC and addition of C18:3n-3 cis promote oxidation of fatty acids.

Keywords:  MDBK cells; metabolic flux; palmitic acid; pyruvate carboxylase; α-linolenic acid

DOI:  https://doi.org/10.1152/physiolgenomics.00141.2024
Blood. 2025 Feb 05. pii: blood.2024026040. [Epub ahead of print]

PSTK inhibition activates cGAS-STING, precipitating ferroptotic cell death in leukemic stem cells.

Lingli He, Ting Zhao, Wei Zhong Leong, Azeem Sharda, Christina Mayerhofer, Shenglin Mei, Gracia M Bonilla, Juan Bautista Menendez-Gonzalez, Karin Gustafsson, Tsuyoshi Fukushima, Trine A Kristiansen, Ji-Won Lee, Yanxin Xu, Lei Chen, Jun Xia, Luis Angel Orozco, Bogdan Budnik, Ruslan Sadreyev, Zhixun Dou, David B Sykes, David T Scadden.

Differentiation arrest and dependence on oxidative metabolism are features shared among genetically diverse acute myeloid leukemias (AML). A phenotypic CRISPR-Cas9 screen in AML identified dependence on phosphoseryl-tRNA kinase (PSTK), an atypical kinase required for the biosynthesis of all selenoproteins. In vivo, PSTK inhibition (PSTKi) impaired AML cell growth and leukemic stem cell self-renewal. Notably, timed pharmacologic PSTKi effectively targeted chemo-resistant AML in murine and patient-derived xenograft models, showing selectivity for malignant cells over normal hematopoietic cells. Mechanistically, PSTKi-induced reactive oxygen species (ROS) triggering mitochondrial DNA release into the cytosol and activated cGAS-STING. This activation in turn disrupted iron metabolism augmenting ROS generation and amplifying ferroptosis. Together, these findings reveal a self-reinforcing PSTK-cGAS-STING-ROS loop culminating in an oxidative crisis and ferroptotic cell death of leukemic stem cells. The data highlight the potential for augmenting standard cancer chemotherapies using timed metabolic intervention to eliminate chemopersisting cells and thereby impede disease relapse.

DOI: https://doi.org/10.1182/blood.2024026040
Public Health Nutr. 2025 Feb 06. 1-21

Adherence to the Mediterranean diet and colorectal cancer risk: a large case control study in the Moroccan population.

Khaoula El Kinany, Zineb Hatime, Achraf El Asri, Abdelilah Benslimane, Meimouna Deoula, Btissame Zarrouq, Pagona Lagiou, Karima El Rhazi.

   OBJECTIVE: The Mediterranean diet (MD) is a dietary pattern associated with several health benefits, including reduction of risk for various cancers. We conducted a study to investigate associations between adherence to the MD and colorectal cancer (CRC) subtype risk among Moroccan adults.
DESIGN: A matched case-control study.
SETTING: The five major university hospitals in Morocco.
PARTICIPANTS: A total of 3032 subjects (1516 CRC patients and 1516 controls) matched on age, sex and center, were recruited between September 2009 and February 2017 at five major hospitals in Morocco. Diet was assessed using a validated Food Frequency Questionnaire (FFQ). Adherence to the Mediterranean diet was assessed through a score, ranging from 0 (no adherence) to 10 (maximal adherence) and divided into three categories (low, middle and high). Conditional logistic regression was performed to calculate multivariable odd ratios (OR) and 95% confidence intervals (CI) with low adherence (score 0-3) as referent, adjusting for potential confounding factors.
RESULTS: Close adherence to the Mediterranean diet (score 6-9) was associated with reduced risk of CRC (ORa = 0.74, 95% CI 0.63-0.86); rectal cancer (ORa = 0.73, 95% CI 0.58- 0.90) and colon cancer (ORa = 0.74, 95% CI 0.60-0.92).
CONCLUSION: Our study, conducted in a southern Mediterranean population, adds to the evidence suggesting a protective effect of MD against CRC risk.

Keywords:  Mediterranean diet; Mediterranean diet score; Morocco; case-control; colorectal cancer

DOI:  https://doi.org/10.1017/S1368980025000199
Obesity (Silver Spring). 2025 Feb 04.

Alternate-day fasting enhanced weight loss and metabolic benefits over pair-fed calorie restriction in obese mice.

Hadia Nawaz, Haneul Lee, Sumin Kang, Hayoon Kim, Wooki Kim, Gwang-Woong Go.

OBJECTIVE: Both alternate-day fasting (ADF) and calorie restriction (CR) are effective weight loss strategies. However, most individuals find it difficult to adhere to CR. Furthermore, CR can induce an excessive loss of not only fat but also muscle mass. This study aimed to compare the effects of ADF and pair-feeding (PF) CR on metabolic pathways underlying obesity in mice with high-fat diet (HFD)-induced obesity.
METHODS: Male C57BL/6N Tac mice (n = 10 per group) were fed an HFD for 8 weeks to establish a diet-induced obesity model. Mice were then continued on the HFD with either alternate-day access to food or PF for the next 8 weeks. We measured body weight, adiposity, plasma biomarkers, and molecular mechanisms involving lipolysis and autophagy.
RESULTS: Both ADF and PF resulted in comparable weight and fat loss. Compared with PF, ADF showed a significant reduction in liver weight and hepatic triglyceride levels. ADF significantly increased plasma ketone body levels and white adipose tissue lipolysis. Compared with PF, ADF tended to activate autophagy elongation and autophagosome formation, which were insignificant.
CONCLUSIONS: These findings indicated that ADF is a promising intervention for metabolic diseases, potentially due to its superior efficacy in promoting ketogenesis and lipolysis compared with PF.

DOI: https://doi.org/10.1002/oby.24211
Br J Nutr. 2025 Feb 03. 1-35

The association between dietary inflammatory potential and risk of total and site-specific colorectal cancer: a systematic review and meta-analysis of observational studies.

Ali Nikparast, Elahe Etesami, Mahshad Shafiee, Fatemeh Javaheri-Tafti, Arefeh Mohajerani, Matin Ghanavati.

  In the last decades, it has been well known that low grade inflammation plays a potential role in the pathogenesis of different cancers. The aim of this systematic review and meta-analysis of observational studies was to evaluate the association between inflammatory potential of diet measured through the Dietary Inflammatory Index (DII), energy-adjusted DII (E-DII), empirical dietary inflammatory pattern (EDIP) and inflammatory score of the diet (ISD) and risk of colorectal cancer (CRC) and site-specific colon cancer. A systematic electronic search of PubMed/Medline, Scopus, the Web of Sciences, and reference lists up to November 21, 2023, was performed. Data were pooled by the generic inverse variance method using random effect model. To assess the heterogeneity of included studies, the I2 index was used. A total of 28 original studies, comprising 2,287,836 participants, were selected to include in this meta-analysis. Pooled results showed a significant association between higher adherence to proinflammatory diet and increased risk of CRC (ES:1.39;95%CI:1.29-1.51;I2=82.9%), colon (ES:1.40;95%CI:1.26-1.55; I²= 73.3%, p<0.01), proximal colon (ES:1.28; 95% CI:1.17-1.40;I²=29.1%), distal (ES:1.50;95%CI:1.30-1.74;I²= 63.5%) and rectal (ES:1.46;95%CI:1.23-1.74;I²=80%). Stratified analysis by type of dietary indices noted that greater adherence to the DII, E-DII, and EDIP were related to significant increase in risk of overall CRC and site-specific colon cancers. Our results highlighted the proposed role of inflammatory protentional of diet as important risk factor for CRC. Adherence to an anti-inflammatory dietary pattern should be recommended to reduce incidence of CRC, globally.

Keywords:  Dietary Inflammatory Index; colorectal cancer; empirical dietary inflammatory pattern; inflammatory indicators

DOI:  https://doi.org/10.1017/S0007114525000121
Eur J Paediatr Neurol. 2025 Jan 28. pii: S1090-3798(25)00008-X. [Epub ahead of print]54 140-146

Harmful metabolic acidosis in children treated by ketogenic diet during prolonged general anesthesia for epilepsy surgery: A single center experience.

Rayann Checri, Severine Gras, Simon Clariot, Anais Chivet, Marie-Thérèse Dangles, Julie Bonheur, Nathalie Dorison, Mathilde Chipaux, Pierre Trouiller, Sarah Ferrand-Sorbets, Jean-Michel Devys, Emmanuel Raffo.

   OBJECTIVE: Management of ketogenic diet (KD) in case of prolonged anesthesia in children.
METHODS: We conducted a retrospective study in the pediatric neurosurgery department of Rothschild Hospital Foundation in France. All the children who underwent long term anesthesia (>4h) in case of neurosurgery for drug resistant pediatric epilepsy surgery between September 2020 and January 2024 were included, excluding patients with suspected metabolic disorder or without blood sample. Children were analyzed in three subgroups: Children under regular diet before surgery constituted the Non-KD group; strict maintenance of KD with no carbohydrate intake during surgery constituted the KD-S group (stringent); carbohydrate intravenous intake during surgery in a patient treated by KD represented the KD-B group (broken).
RESULTS: 22 patients were included, among whom 6 under ketogenic diet (KD). After 4 h of anesthesia, children maintained in strict ketogenic diet (KD-S, n = 3) exhibited non-lactic metabolic acidosis (pH 7.13 vs 7.34, p = 1.38x10-9) associated with an increased anionic gap (17.1 mM vs 9.6 mM, p = 1.58 x10-4).
SIGNIFICANCE: Current recommendations for anesthesia during long term anesthesia (>4h) with strict no-carbohydrate intake during anesthesia in case ok KD may be at risk of life-threatening metabolic acidosis, in a context of absence of protocolized monitoring of variations in hyperketosis throughout a prolonged fast. A KD-management protocol, including routine monitoring of ketosis in addition to usual monitoring (lactacidemia, kaliemia and glycemia), and low carbohydrates intravenous perfusion throughout prolonged general anesthesia, should be implemented throughout prolonged general anesthesia, especially for infants younger than 2 years.

Keywords:  Epilepsy surgery; General anesthesia; Ketogenic diet; Metabolic acidosis; Severe hypokaliemia

DOI:  https://doi.org/10.1016/j.ejpn.2025.01.008
Cell Metab. 2025 Feb 04. pii: S1550-4131(24)00525-4. [Epub ahead of print]37(2): 305-306

Fueling metabolic disruption via FMD to boost chemotherapy in TNBC.

Marcus D Goncalves, Neil M Iyengar.

Triple-negative breast cancer (TNBC) is highly glycolytic and lacks effective biomarkers for therapy response. The BREAKFAST trial showed that a fasting-mimicking diet (FMD) improved pathological complete response (pCR) rates to 56.6% compared to historical chemotherapy averages (30%-40%), with minimal severe adverse events. FMD's metabolic and immune-modulating effects warrant further study with immunotherapy.

DOI: https://doi.org/10.1016/j.cmet.2024.12.015
Commun Med (Lond). 2025 Feb 04. 5(1): 36

Multi-dimensional evidence from the UK Biobank shows the impact of diet and macronutrient intake on aging.

Chen Zhu, Youfa Wang, Xiaosong Yang, Qiran Zhao, Wenyan Xu, Xiaolu Wang, Yanjun Liang, Qihui Chen, Shenggen Fan.

BACKGROUND: The role of diet in aging is crucial, yet research findings on how specific diets influence human aging remain inconsistent. Understanding the relationship between dietary factors and aging could inform interventions to promote healthier aging outcomes.
METHODS: We analyzed data from the UK Biobank baseline survey and a 24-hour dietary assessment survey to investigate the association between diet and aging. The study examined 18 individual food intakes, 6 dietary patterns, 3 macronutrient intakes, and 3 dietary quality scores. High-dimensional Fixed Effects (HDFE) models were used to assess associations between dietary factors and aging measures, including telomere length, phenotypic age, and brain grey/white matter volumes. Multivariable Mendelian Randomization (MVMR) was employed to explore causal links between macronutrient consumption and aging outcomes.
RESULTS: Our results show that healthier diets are generally associated with improved aging outcomes from HDFE analyses. Plant-based food consumption correlates with increased telomere length and reduced phenotypic age, while animal-based food intake is linked to adverse aging effects. MVMR results confirm the causal benefits of carbohydrate intake, including reductions in phenotypic age (β = -0.0025; 95% CI = [-0.0047, -0.0003]; p = 0.0253) and increases in whole-brain grey matter volume (β = 0.0262; 95% CI = [0.007, 0.046]; p = 0.0087). The latter association remains significant after multiple testing correction.
CONCLUSIONS: This study underscores the significant role of diet in biological aging and provides robust evidence for the benefits of carbohydrate intake in promoting healthier aging. These findings highlight the potential of dietary interventions to improve aging-related outcomes.

DOI: https://doi.org/10.1038/s43856-025-00754-5
Synthesis (Stuttg). 2024 Sep;56(18): 2909-2917

Design, Synthesis, and Assessment of Tricarboxylic Acid Cycle Probes.

Joseph Chen, Darrian Chao, Uyen Phuong Tran, Kelvin L Billingsley.

  Hyperpolarized 13C magnetic resonance spectroscopy can provide unique insights into metabolic activity in vivo. Despite the advantages of this technology, certain metabolic pathways such as the tricarboxylic acid (TCA) cycle are more challenging to examine due to the limitations associated with currently available hyperpolarized 13C probes. In this report, we systematically employ computational analyses, synthetic techniques, and in vitro studies to facilitate the design of new chemical probes for the TCA cycle. This platform allows for the rapid identification of probe scaffolds that are amenable to hyperpolarized 13C experimentation. Using these results, we have developed two 13C-labeled chemical probes, [1,4-13C2]-dipropyl succinate and [1,4-13C2]-diallyl succinate, which are employed in hyperpolarized 13C metabolic studies.

Keywords:  chemical probe; esterase; esterification; hyperpolarized 13C; in vitro assays; metabolism; tricarboxylic acid cycle

DOI:  https://doi.org/10.1055/a-2335-8736
Biophotonics Discov. 2025 Jan;pii: 012702. [Epub ahead of print]2(1):

Optical imaging provides flow-cytometry-like single-cell level analysis of HIF-1α-mediated metabolic changes in radioresistant head and neck squamous carcinoma cells.

Jing Yan, Carlos Frederico Lima Goncalves, Pranto Soumik Saha, Cristina M Furdui, Caigang Zhu.

   Significance: Radioresistance remains a significant problem for head and neck squamous cell carcinoma (HNSCC) patients. To mitigate this, the cellular and molecular pathways used by radioresistant HNSCC that drive recurrence must be studied.
Aim: We aim to demonstrate optical imaging strategies to provide flow cytometry-like single-cell level analysis of hypoxia-inducible factor 1-alpha (HIF-1α)-mediated metabolic changes in the radioresistant and radiosensitive HNSCC cells but in a more efficient, cost-effective, and non-destructive manner. Through both optical imaging and flow cytometry studies, we will reveal the role of radiation-induced HIF-1α overexpression and the following metabolic changes in the radioresistance development for HNSCC.
Approach: We optimized the use of two metabolic probes: 2-[N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl) amino]-2-deoxy-D-glucose (2-NBDG) (to report glucose uptake) and Tetramethylrhodamine ethyl ester (TMRE) (to report mitochondrial membrane potential) with both a standard fluorescence microscope and a flow cytometry device, to report the changes in metabolism between radioresistant (rSCC-61) and radiosensitive (SCC-61) HNSCC cell lines under radiation stresses with or without HIF-1α inhibition.
Results: We found that the matched HNSCC cell lines had different baseline metabolic phenotypes, and their metabolism responded differently to radiation stress along with significantly enhanced HIF-1α expressions in the rSCC-61 cells. HIF-1α inhibition during the radiation treatment modulates the metabolic changes and radio-sensitizes the rSCC-61 cells. Through these studies, we demonstrated that a standard fluorescence microscope along with proper image processing methods can provide flow cytometry-like single-cell level analysis of HIF-1α-mediated metabolic changes in the radioresistant and radiosensitive HNSCC cells.
Conclusions: Our reported optical imaging strategies may enable one to study the role of metabolism reprogramming in cancer therapeutic resistance development at the single-cell level in a more efficient, cost-effective, and non-destructive manner. Our understanding of radiation resistance mechanisms using our imaging methods will offer opportunities to design targeted radiotherapy for improved treatment outcomes for HNSCC patients.

Keywords:  fluorescence microscopy; head and neck squamous cell carcinoma; optical metabolic imaging; radiation therapy; tumor metabolism

DOI:  https://doi.org/10.1117/1.bios.2.1.012702
Cell. 2025 Jan 10. pii: S0092-8674(24)01420-X. [Epub ahead of print]

Rhodoquinone carries electrons in the mammalian electron transport chain.

Jonathan Valeros, Madison Jerome, Tenzin Tseyang, Paula Vo, Thang Do, Diana Fajardo Palomino, Nils Grotehans, Manisha Kunala, Alexandra E Jerrett, Nicolai R Hathiramani, Michael Mireku, Rayna Y Magesh, Batuhan Yenilmez, Paul C Rosen, Jessica L Mann, Jacob W Myers, Tenzin Kunchok, Tanner L Manning, Lily N Boercker, Paige E Carr, Muhammad Bin Munim, Caroline A Lewis, David M Sabatini, Mark Kelly, Jun Xie, Michael P Czech, Guangping Gao, Jennifer N Shepherd, Amy K Walker, Hahn Kim, Emma V Watson, Jessica B Spinelli.

  Ubiquinone (UQ), the only known electron carrier in the mammalian electron transport chain (ETC), preferentially delivers electrons to the terminal electron acceptor oxygen (O2). In hypoxia, ubiquinol (UQH2) diverts these electrons onto fumarate instead. Here, we identify rhodoquinone (RQ), an electron carrier detected in mitochondria purified from certain mouse and human tissues that preferentially delivers electrons to fumarate through the reversal of succinate dehydrogenase, independent of environmental O2 levels. The RQ/fumarate ETC is strictly present in vivo and is undetectable in cultured mammalian cells. Using genetic and pharmacologic tools that reprogram the ETC from the UQ/O2 to the RQ/fumarate pathway, we establish that these distinct ETCs support unique programs of mitochondrial function and that RQ confers protection upon hypoxia exposure in vitro and in vivo. Thus, in discovering the presence of RQ in mammals, we unveil a tractable therapeutic strategy that exploits flexibility in the ETC to ameliorate hypoxia-related conditions.

Keywords:  electron transport chain; hypoxia; ischemia; metabolism; mitochondria; rhodoquinone

DOI:  https://doi.org/10.1016/j.cell.2024.12.007
Biochem Biophys Rep. 2025 Mar;41 101894

Resistance to FLT3 inhibitors involves different molecular mechanisms and reduces new DNA synthesis.

Jingmei Yang, Ran Friedman.

  Acute myeloid leukaemia (AML) is a hard to treat blood cancer. Mutations in FLT3 are common among the genetic aberrations that characterise the cancer. Patients initially react to FLT3 inhibitors but drug resistance is a hinder to successful therapy. To better understand the mechanisms leading to drug resistance, we generated four AML cell lines resistant to the inhibitors gilteritinib or FF-10101, and explored their resistance mechanisms. We further tested whether the novel inhibitor Chen-9u could be used to limit cell growth. The results showed that each of the four resistant cell lines became resistant through a different mechanism. Resistant cells showed decreased FLT3 and increased NRAS pathway activity and reduced DNA synthesis due to decrease in CDK4 activity. Resistance mechanisms included resistance mutations in FLT3 (C695F and N701K), and a novel mutation in NRAS (G12C). In a fourth line, resistance might have developed through a MYCN mutation. Cell growth was inhibited by Chen-9u and resistant clones could not be obtained with this inhibitor. The results highlight opportunities and limitations. On the one hand, resistant cells were produced due to different mechanisms, showing the versatility of tumour cells. Furthermore, resistance developed to the most advanced inhibitors, one of which is covalent and the other non-covalent but highly specific. On the other hand, it is shown that DNA synthesis is reduced, which means that resistance has evolutionary consequences. Finally, the novel drug-resistant cell lines may serve as useful models for better understanding of the cellular events associated with inherent and acquired drug resistance.

Keywords:  Acute myeloid leukemia; CDK4; DNA sequencing; Drug resistance; FF-10101; FLT3; Gilteritinib; NRAS

DOI:  https://doi.org/10.1016/j.bbrep.2024.101894
Heliyon. 2025 Jan 30. 11(2): e41607

The safety and efficacy of a protein-free diet with ketoacid analogues in chronic kidney disease-affected diabetic rats.

Ahmed El-Sayed Nour El-Deen, Adel Shallaby, Abdel Kader Ibrahim, Mohammed Abdel Aziz Mohammed, Ahmad Taha, Mohamed Zaeim Hafez Ahmed, Muhammad Abdelbaeth Elfiky, Ahmed A Abd El-Rhman, Ahmed F Abdel Ghany, Almoatazbellah Mahmoud Elsayed, Ahmed Noaman Ali, Ali Abdeslam.

   Background: Diabetic nephropathy (DN) is a common vascular complication of diabetes Miletus (DM) that require weight control and dietary restrictions, especially for protein. A protein-restricted diet with ketoacid analogs (KA) reduces the intake of nitrogen while avoiding the harmful consequences of inadequate dietary protein intake.
Objective: This study aimed to investigate the efficacy and safety of a protein-free diet with ketoacid analogs in chronic kidney disease (CKD)-affected diabetic rats.
Material and methods: Sixty adult male albino rats were grouped into six equal groups (G): G (1) Control group, G (2) Normal rats. Received low protein diet, G (3) Diabetic control rats. Received standard diet, G (4) Diabetic rats. Received low protein diet for 12 weeks, G (5) Diabetic received α-keto amino acids (KAA) with a low protein diet and G (6) Diabetic received α-keto amino acids with protein-free diet. Blood sample was used to assess blood glucose (mg/dl), insulin (pmol/L), urea (mg/dl), creatinine (mg/dl), total cholesterol (TC) (mg/dl), LDL (mg/dl), HDL (mg/dl), triglycerides (TG) (mg/dl), and albumin (mg/dl) levels.
Results: A significant decrease in blood glucose, serum total cholesterol, LDL, triglycerides, serum urea and creatinine were observed while insulin level, albumin, glomerular filtration rate (GFR), urine volume and HDL were significantly increased in group six.
Conclusion: A protein-free diet containing KAA improves renal function, lowers blood glucose levels, maintains body weight, and does not worsen nutritional status in DN over time.

Keywords:  Diabetes; Ketoacid and protein-free diet; Kidney disease; Protein diet

DOI:  https://doi.org/10.1016/j.heliyon.2024.e41607
Front Oncol. 2024 ;14 1532857

Mitochondrial abnormalities as a target of intervention in acute myeloid leukemia.

Elissa Tjahjono, Megan R Daneman, Bernadetta Meika, Alexey V Revtovich, Natalia V Kirienko.

  Acute myeloid leukemia (AML) is an aggressive hematological malignancy; it is the most common acute leukemia in adults. AML prognosis is often poor, and relapse often occurs after initial remission. Recurrent genetic abnormalities underlying this disease and the presence of leukemic stem cells complicate disease treatment. However, the complex metabolic reprogramming that enables the unrestrained cell growth seen in these cells may also be their Achilles' heel. In these cells, mitophagy operates as a double-edged sword. On one hand, it provides a source of building blocks for further cell division and serves as a method for removing damaged organelles, promoting cell survival. However, the profound metabolic changes to mitochondria also render these organelles more sensitive to damage and place them precariously close to excess mitophagic activation. This review discusses the dual role mitophagy plays in AML survival, the importance of targeting mitophagy to treat AML, and current progress in the area. The discovery and mechanism of action of multiple compounds that were used to inhibit or stimulate mitophagy and their effects on AML survival are also described. Further, we explore the combination strategy of mitophagy-targeting compounds with existing and/or novel chemotherapeutics to eradicate AML and discuss strategies to uncover new drug targets and novel mitochondria-targeting drugs.

Keywords:  acute myeloid leukemia; glutaminolysis; leukemic stem cells; mitochondria; mitophagy; oxidative phosphorylation

DOI:  https://doi.org/10.3389/fonc.2024.1532857
Biochimie. 2025 Jan 31. pii: S0300-9084(25)00024-0. [Epub ahead of print]

The pentose phosphate pathway (PPP) in the glioma metabolism: A potent enhancer of malignancy.

Cristina Trejo-Solís, Ángel Escamilla-Ramírez, Saúl Gómez-Manzo, Rosa Angélica Castillo-Rodriguez, Francisca Palomares-Alonso, Carlos Castillo-Pérez, Dolores Jiménez-Farfán, Aurora Sánchez-García, Juan Carlos Gallardo-Pérez.

  The glioma hallmark includes reprogramming metabolism to support biosynthetic and bioenergetic demands, as well as to maintain their redox equilibrium. It has been suggested that the pentose phosphate pathway (PPP) and glycolysis are directly involved in the dynamics and regulation of glioma cell proliferation and migration. The PPP is implicated in cellular redox homeostasis and the modulation of signaling pathways, which play a fundamental role in the progression of tumors to malignant grades, metastasis, and drug resistance. Several studies have shown that in glioblastoma cells, the activity, expression, and metabolic flux of some PPP enzymes increase, leading to heightened activity of the pathway. This generates higher levels of DNA, lipids, cholesterol, and amino acids, favoring rapid cell proliferation. Due to the crucial role played by the PPP in the development of glioma cells, enzymes from this pathway have been proposed as potential therapeutic targets. This review summarizes and highlights the role that the PPP plays in glioma cells and focuses on the key functions of the enzymes and metabolites generated by this pathway, as well as the regulation of the PPP. The studies described in this article enrich the understanding of the PPP as a therapeutic tool in the search for pharmacological targets for the development of a new generation of drugs to treat glioma.

Keywords:  Glioblastoma; Metabolites; Pathway signaling; Pentose phosphate pathway

DOI:  https://doi.org/10.1016/j.biochi.2025.01.013
bioRxiv. 2025 Jan 24. pii: 2025.01.22.634215. [Epub ahead of print]

Adaptive Plasticity Tumor Cells Modulate MAPK-Targeting Therapy Response in Colorectal Cancer.

Oscar E Villarreal, Yixin Xu, Ha Tran, Annette Machado, Dionne Prescod, Amanda Anderson, Rosalba Minelli, Mike Peoples, Alejandro Hernandez Martinez, Hey Min Lee, Chi Wut Wong, Natalie Fowlkes, Preeti Kanikarla, Alexey Sorokin, Jumanah Alshenaifi, Olu Coker, Kangyu Lin, Chris Bristow, Andrea Viale, John Paul Shen, Christine Parseghian, Joseph R Marszalek, Ryan Corcoran, Scott Kopetz.

MAPK pathway inhibitors (MAPKi) are increasingly used in the treatment of advanced colorectal cancer, but often produce short-lived responses in patients. Although acquired resistance by de novo mutations in tumors have been found to reduce response in some patients, additional mechanisms underlying the limited response durability of MAPK targeting therapy remain unknown. Here, we denote new contributory tumor biology and provide insight on the impact of tumor plasticity on therapy response. Analysis of MAPKi treated patients revealed activation of stemness programs and increased ASCL2 expression, which are associated with poor outcomes. Greater ASCL2 with MAPKi treatment was also seen in patient-derived CRC models, independent of driver mutations. We find ASCL2 denotes a distinct cell population, arising from phenotypic plasticity, with a proliferative, stem-like phenotype, and decreased sensitivity to MAPKi therapy, which were named adaptive plasticity tumor (APT) cells. MAPK pathway suppression induces the APT phenotype in cells, resulting in APT cell enrichment in tumors and limiting therapy response in preclinical and clinical data. APT cell depletion improved MAPKi treatment efficacy and extended MAPKi response durability in mice. These findings uncover a cellular program that mitigates the impact of MAPKi therapies and highlights the importance of addressing tumor plasticity to improve clinical outcomes.

DOI: https://doi.org/10.1101/2025.01.22.634215
bioRxiv. 2025 Jan 24. pii: 2025.01.23.633049. [Epub ahead of print]

Oxidative Phosphorylation (OXPHOS) Promotes the Formation and Growth of Melanoma Lung and Brain Metastases.

Renato A Guerrieri, Grant M Fischer, David A Kircher, Aron Y Joon, Jacob R Cortez, Allie H Grossman, Courtney W Hudgens, Debora A Ledesma, Rossana Lazcano, Christian Yb Onana, Barbara G Knighton, Swaminathan Kumar, Qianghua Hu, Y N Vashisht Gopal, Jennifer L McQuade, Wanleng Deng, Lauren E Haydu, Jeffrey E Gershenwald, Alexander J Lazar, Michael T Tetzlaff, Sheri L Holmen, Michael A Davies.

Melanoma mortality is driven by the formation and growth of distant metastases. Here, we interrogated the role of tumor oxidative phosphorylation (OXPHOS) in the formation of distant metastases in melanoma. OXPHOS was the most upregulated metabolic pathway in primary tumors that formed distant metastases in the RCAS-TVA mouse model of spontaneous lung and brain metastases, and in melanoma patients that developed brain or other distant metastases. Knockout of PGC1α in melanocytes in the RCAS-TVA melanoma mouse model had no impact on primary tumor formation, but markedly reduced the incidence of lung and brain metastases. Genetic knockout of a component of electron transport chain complex I, NDUFS4, in B16-F10 and D4M-UV2 murine melanoma cell lines did not impact tumor incidence following subcutaneous, intravenous, or intracranial injection, but decreased tumor burden specifically in the lungs and brain. Together, these data demonstrate that OXPHOS is critical for the formation of metastases in melanoma.
STRUCTURED ABSTRACT: Purpose: Melanoma mortality is driven by the formation and growth of distant metastases. However, the process and pathogenesis of melanoma metastasis remain poorly understood. Here, we interrogate the role of tumor oxidative phosphorylation (OXPHOS) in the formation of distant metastases in melanoma.Experimental Design: This study includes (1) new RNA-seq analysis of primary melanomas from patients characterized for distant metastasis events; (2) RNA-seq analysis and functional testing of genetic OXPHOS inhibition (PGC1α KO) the RCAS-TVA model, which is the only existing immunocompetent murine model of autochthonous lung and brain metastasis formation from primary melanoma tumors; and (3) functional experiments of genetic OXPHOS inhibition (NDUFS4 KO) in the B16-F10 and D4M-UV2 murine melanoma cell lines, including evaluation of subcutaneous, lung, and brain metastatic site dependencies.Results: OXPHOS was the most upregulated metabolic pathway in primary tumors that formed distant metastases in the RCAS-TVA mouse model of spontaneous lung and brain metastases, and in melanoma patients that developed brain or other distant metastases. Knockout of PGC1a in melanocytes in the RCAS-TVA melanoma mouse model had no impact on primary tumor formation, but markedly reduced the incidence of lung and brain metastases. Genetic knockout of a component of electron transport chain complex I, NDUFS4, in B16-F10 and D4M-UV2 murine melanoma cell lines did not impact tumor incidence following subcutaneous, intravenous, or intracranial injection, but decreased tumor burden specifically in the lungs and brain.Conclusions: Together, these data demonstrate that OXPHOS is critical for the formation of metastases in melanoma.
TRANSLATIONAL RELEVANCE: Melanoma is the most aggressive form of skin cancer. One hallmark of this disease is a high risk of distant metastasis formation. The process and pathogenesis of metastasis in this disease remain poorly understood and there is controversy regarding the role of oxidative phosphorylation (OXPHOS) in melanoma metastasis. This study incorporates RNAseq analysis of primary melanoma tumors from patients characterized for distant metastasis events, RNAseq analysis of the only existing immunocompetent murine model of autochthonous lung and brain metastasis formation from primary melanoma tumors, and functional testing in multiple syngeneic models of melanoma at different tissue sites. This integrated analysis consistently demonstrates that melanoma OXPHOS promotes distant metastasis to the lungs and brain, two of the most common and clinically relevant sites of melanoma metastasis. This improved understanding of tumor OXPHOS may represent novel vulnerabilities for therapeutics development and surveillance/preventative strategies for melanoma metastasis.

DOI: https://doi.org/10.1101/2025.01.23.633049
Pharmacol Res. 2025 Feb 03. pii: S1043-6618(25)00068-4. [Epub ahead of print]213 107643

Glutamine deprivation confers immunotherapy resistance by inhibiting IFN-γ signaling in cancer cells.

Zhiwei Yuan, Taiyan Yu, Xu Wang, Kelin Meng, Tianlai Wang, Boyu Wang, Yu Xi, Congjian Wang, Chenxi Zeng, Shaojie Hu, Yitao Tian, Hui Xiong, Qi Wang, Wenbin Zou, Xue Wang, Yi Gao, Xiangning Fu, Lequn Li.

  Glutamine metabolism is emerging as a target for improving immunotherapy efficacy. However, the outcomes remain inconclusive. Given that the tumor-intrinsic response to interferon-γ (IFN-γ) is a key determinant of immunotherapy efficacy, we investigated whether and how glutamine deprivation in cancer cells affects their response to IFN-γ. By using human lung cancer cell lines, patient-derived tumor explants, and a syngeneic mouse model of lung cancer, we demonstrated that glutamine deprivation reduced the IFN-γ-driven response in cancer cells by promoting autophagy-dependent IFN-γ receptor (IFNGR1) degradation and rendering tumors resistant to anti-PD-1 or anti-PD-L1 therapy. Treatment with V9302, an inhibitor of the alanine-serine-cysteine transporter (ASCT2), enhanced the IFN-γ-driven response of cancer cells and increased the efficacy of PD-1 blockade therapy. Mechanistic analysis revealed that V9302 inhibited autophagy by impairing lysosomal activity independent of glutamine deprivation, likely because of its physiochemical properties, thereby preventing IFNGR1 degradation. Moreover, V9302 also increased Glut1 expression through the inhibition of lysosomal pathway-dependent degradation of Glut1 and consequently increased cancer cell glucose uptake, in turn retaining the levels of intracellular alpha-ketoglutarate (α-KG) and ATP, which are involved in maintaining IFN-γ signal transduction in cancer cells. In support of these findings, targeting lysosomal activity with chloroquine (CQ) also increased IFNGR1 expression and the IFN-γ-driven response in cancer cells. The administration of CQ increased the sensitivity of ASCT2-deficient tumors to anti-PD-L1 therapy. Glutamine deprivation per se leads to resistance to immunotherapy, whereas V9302 treatment results in increased immunotherapy efficacy through impaired lysosomal activity, which is independent of glutamine deprivation.

Keywords:  Autophagy; Glutamine metabolism; IFN-γ signaling; Immunotherapy; Non-small cell lung cancer; V9302

DOI:  https://doi.org/10.1016/j.phrs.2025.107643
Nutr Rev. 2025 Feb 03. pii: nuae222. [Epub ahead of print]

Dietary Acid Load and Human Health: A Systematic Review and Meta-analysis of Observational Studies.

Maryam Abbastabar, Zahra Mohammadi-Pirouz, Shabnam Omidvar, Afsaneh Bakhtiari, Francesca L Crowe, Mahdi Sepidarkish.

   CONTEXT: Dietary acid load (DAL) plays an important role in different aspects of human health.
OBJECTIVE: The aim of this meta-analysis was to systematically synthesize the observational evidence reporting on the associations between the DAL (represented by a potential renal acid load [PRAL] and net endogenous acid production [NEAP]) and a range of health outcomes.
DATA SOURCES: A systematic search of Medline (via PubMed), EMBASE, Scopus, and Web of Science was performed to identify eligible studies.
DATA EXTRACTION: Study screening and risk-of-bias assessment were conducted by 2 independent reviewers.
DATA ANALYSIS: The credibility of each outcome was graded based on predefined criteria: pooled effect size with corresponding 95% CI, 95% prediction interval, heterogeneity, small-study effect, and excess significance bias. In total, 118 observational studies (case-control [n = 22], cross-sectional [n = 65], and cohort [n = 31]) on 38 outcomes were included, incorporating a total population of 1 014 081 participants. Overall, 21/37 and 20/38 of the outcomes reported statistically significant effect sizes for PRAL and NEAP, respectively. The credibility of the evidence for PRAL was rated convincing (class I) for type 2 diabetes (T2D), and as highly suggestive evidence (class II) for overall cancer and systolic blood pressure. By assessing the credibility of the evidence for NEAP, T2D and overall cancer presented convincing evidence (class I) and breast cancer presented highly suggestive evidence (class II). The remaining outcomes presented class III (suggestive) or lower evidence (weak or no association).
CONCLUSION: The higher acid-forming potential of diet was associated with a higher risk of T2D and overall cancer. Since this meta-analysis included observational studies and some of the associations were graded as weak, caution should be exercised in interpreting these associations. Further cohort studies are required with consideration of other factors that can cause biases.
SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42022336050.

Keywords:  NEAP; PRAL; dietary acid load

DOI:  https://doi.org/10.1093/nutrit/nuae222
Discov Oncol. 2025 Feb 05. 16(1): 120

Causal associations between dietary habits and liver cancer risk: a two-sample Mendelian randomization study.

Wen-Hao Hu, Jia-An Sun, Chang Liu.

   BACKGROUND: Liver cancer is among the most prevalent cancers worldwide and is the second leading cause of cancer-related death. Epidemiological evidence suggests a potential correlation between dietary habits and the incidence of liver cancer. However, establishing a definitive causal relationship remains uncertain. Mendelian randomization (MR) is frequently employed to investigate the causal link between exposure and results.
AIM: This research focuses primarily on exploring and confirming whether there is a causal connection between dietary choices and the risk of liver cancer.
METHODS: Exposure data, encompassing various dietary habits such as the consumption of dried and fresh fruits, both cooked and raw vegetables, types of fish (oily and nonoily), and beverages such as tea and coffee, as well as different meats (poultry, beef, pork, and processed), were obtained from the UK Biobank. Conversely, outcome data were derived from the FinnGen study. Inverse variance weighting (IVW) was predominantly employed to assess the causal relationship. To ensure the validity of our findings, rigorous tests for heterogeneity and horizontal pleiotropy were conducted.
RESULTS: Our MR study findings revealed a significant association, indicating that genetically influenced oily fish intake is linked to a lower risk of liver cancer (OR = 0.160, 95% CI 0.026-0.968; P = 0.046). However, no substantial causal connections between liver cancer and the intake of other dietary habits were observed. Importantly, our two-sample MR investigations indicated no considerable pleiotropy effects in the instrumental variables (IVs).
CONCLUSION: In summary, our findings suggest a potential protective effect of oily fish intake against liver cancer, emphasizing the need for further studies to validate these results.

Keywords:  Cancer incidence risk; Causal effect; Dietary habits; Liver cancer; Mendelian randomization

DOI:  https://doi.org/10.1007/s12672-025-01885-w
AAPS J. 2025 Feb 03. 27(1): 38

Impact of Dapagliflozin on Hepatic Lipid Metabolism and a Dynamic Model of Ketone Body Levels.

Zhijie Wan, Ming Yuan, Ziao Liu, Yuan Cai, Hua He, Kun Hao.

  The rising prevalence of metabolic-associated steatotic liver disease emphasizes the need to understand its lipid metabolism. Dapagliflozin may improve hepatic steatosis but could also increase the risk of ketoacidosis by elevating β-hydroxybutyrate (KB) levels. This study investigates dapagliflozin's effects on hepatic lipid metabolism and quantifies KB levels in vivo. Male Sprague-Dawley rats were fed either a normal diet or a high-fat diet (HFD) for 12 weeks. The HFD rats were then divided into four subgroups to receive vehicle, 0.5 mg/kg, 1 mg/kg, and 3 mg/kg of dapagliflozin for four weeks. Free fatty acids (FFA) and KB levels were monitored, while protein and gene expression were analyzed. And a dynamic model of KB was developed for humans based on preclinical data. Dapagliflozin decreased body weight and visceral fat in HFD rats, increasing KB by upregulating CPT1a, HMGCS2, and HMGCL, and downregulating ACC. These changes correlated with reduced liver/fat index, liver pathology score, and oil-red staining area. A pharmacokinetic/pharmacodynamic (PK/PD) model was created from preclinical data to quantify KB levels in rats and validated in humans. Dapagliflozin reduces hepatic steatosis by enhancing fatty acid β-oxidation and ketogenesis and inhibiting fat synthesis. A dynamic model accurately predicts ketone body levels in treated individuals.

Keywords:  dapagliflozin; dynamic model; hepatic steatosis; ketone body

DOI:  https://doi.org/10.1208/s12248-025-01024-x
Cancer Biol Ther. 2025 Dec;26(1): 2460252

The mitochondria as an emerging target of self-renewal in T-cell acute lymphoblastic leukemia.

Majd A Al-Hamaly, Evelyn Winter, Jessica S Blackburn.

  Acute lymphocytic leukemia (ALL) is the most common leukemia in children, with the T-cell subtype (T-ALL) accounting for 15% of those cases. Despite advancements in the treatment of T-ALL, patients still face a dismal prognosis following their first relapse. Relapse can be attributed to the inability of chemotherapy agents to eradicate leukemia stem cells (LSC), which possess self-renewal capabilities and are responsible for the long-term maintenance of the disease. Mitochondria have been recognized as a therapeutic vulnerability for cancer stem cells, including LSCs. Mitocans have shown promise in T-ALL both in vitro and in vivo, with some currently in early-phase clinical trials. However, due to challenges in studying LSCs in T-ALL, our understanding of how mitochondrial function influences self-renewal remains limited. This review highlights the emerging literature on targeting mitochondria in diverse T-ALL models, emphasizing specific mitochondrial vulnerabilities linked to LSC self-renewal and their potential to significantly improve T-ALL treatment.

Keywords:  Mitochondria; OXPHOS; T-ALL; cancer stem cells; leukemia stem cells; metabolism; self-renewal

DOI:  https://doi.org/10.1080/15384047.2025.2460252
Blood. 2025 Feb 07. pii: blood.2024026700. [Epub ahead of print]

Venetoclax plus Daunorubicin and Cytarabine for Newly Diagnosed Acute Myeloid Leukemia: Results of a Phase 1b Study.

Ioannis Mantzaris, Mendel Goldfinger, Matan Uriel, Aditi Shastri, Nishi Shah, Kira Gritsman, Noah Kornblum, Lauren C Shapiro, Alejandro Sica, Anne Munoz, Nicole Chambers, Aradhika Dhawan, Jhannine Alyssa Verceles, Karen Fehn, Balda Tirone, Lamisha Shah, Shaunmonique Clark, Chenxin Zhang, Mimi Y Kim, Dennis L Cooper, Amit Verma, Marina Y Konopleva, Eric J Feldman.

Venetoclax combined with intensive chemotherapy shows promise for untreated acute myeloid leukemia (AML), but its integration with the '7+3' regimen remains underexplored. In a phase 1b study (NCT05342584), we assessed the safety and efficacy of venetoclax with daunorubicin and cytarabine in newly diagnosed AML patients. Thirty-four patients (median age 59 years; 62% non-white) received venetoclax at escalating durations (8, 11, or 14 days). Adverse events included febrile neutropenia (100%), sepsis (29%), and enterocolitis (23.5%), with no induction deaths. Median recovery times for neutrophils (>1.0K/uL) and platelets (>100K/uL) were under 30 days. Composite complete remission (CRc) was achieved in 85.3% of patients, with 86.2% being measurable residual disease (MRD)-negative. Responses spanned all ELN2022 risk categories. With a median follow-up of 9.6 (2-20) months, median duration of response, event-free survival and overall survival were not reached. Venetoclax (400 mg) combined with '7+3' chemotherapy was safe and effective in achieving MRD-negative remissions across all durations. Ven dose optimization is being explored in the expansion phase of this trial. Future multicenter studies should confirm our findings.

DOI: https://doi.org/10.1182/blood.2024026700
Nat Commun. 2025 Feb 04. 16(1): 1358

Targeting ceramide transfer protein sensitizes AML to FLT3 inhibitors via a GRP78-ATF6-CHOP axis.

Xiaofan Sun, Yue Li, Juan Du, Fangshu Liu, Caiping Wu, Weihao Xiao, Guopan Yu, Xiaowei Chen, Robert Peter Gale, Hui Zeng.

Sphingolipid, ceramide for example, plays an essential role in regulating cancer cell death. Defects in the generation and metabolism of ceramide in cancer cells contribute to tumor cell survival and resistance to chemotherapy. Ceramide Transfer Protein (CERT) determines the ratio of ceramide and sphingomyelin in cells. Targeting CERT sensitizes solid cancer cells to chemotherapy. However, whether targeting CERT to induce ceramide accumulation thereby improving AML therapy efficiency remains elusive. Here, we show that knocking down CERT inhibits the growth and promotes the apoptosis of AML cells carrying FLT3-ITD mutation. Combining CERT inhibitor with FLT3 inhibitor exhibits synergistic effects on FLT3-ITD mutated acute myeloid leukemia (AML) cells. Additionally, co-treatment of HPA-12 and Crenolanib is effective in FLT3-ITD+ and FLT3-TKD+ AML patients. The synergistic effects are found to be mediated by the endoplasmic reticulum stress-GRP78/ATF6/CHOP axis and mitophagy. Our data provide an effective strategy to enhance the efficacy of FLT3 inhibitors in AML.

DOI: https://doi.org/10.1038/s41467-025-56520-7
Int J Food Sci Nutr. 2025 Feb 05. 1-11

Association between Healthy Eating Index 2015 and metabolic syndrome among US cancer survivors: evidence from NHANES 2005-2016.

Jiazhen Yao, Xiaohong Chen, Yirong Xin, Fang Meng, Xiaoyan Zhong, Hanzhong Cao, Junlan Qiu, Xiaochen Shu.

  Our study examined the relationship between diet quality and the prevalence of metabolic syndrome (MetS) among 1779 U.S. cancer survivors using data from the National Health and Nutrition Examination Survey (NHANES, 2005-2016). Diet quality was assessed using the Healthy Eating Index 2015 (HEI-2015). Higher HEI-2015 scores were linked to significantly lower MetS prevalence (OR: 0.51, 95% CI: 0.32-0.80). Specifically, a higher intake of seafood and plant proteins, and fatty acids, coupled with a reduced intake of added sugars, was associated with decreased odds of MetS prevalence (OR: 0.93; 95% CI, 0.86-0.99) in cancer survivors. Additionally, a better diet quality was linked to lower prevalence of high waist circumference, elevated triglycerides, reduced high-density lipoprotein (HDL) cholesterol and high fasting glucose levels (OR, 0.44; 95% CI, 0.27-0.72). These results suggest that adopting healthy dietary habits may prevent MetS in cancer survivors.

Keywords:  Healthy Eating Index 2015; NHANES; cancer survivors; diet; metabolic syndrome

DOI:  https://doi.org/10.1080/09637486.2025.2461144
Front Nutr. 2025 ;12 1539401

Association of dietary intake with cancer of the digestive system: a cross-sectional study.

Xinxin Qin, Litao Ge, Song Wu, Wei Li.

   Background: In recent years, the incidence of cancers of the digestive system has been increasing, posing a severe threat to the lives and health of people around the world, and has become one of the leading causes of cancer deaths worldwide. The three most common cancers of the digestive system include gastric, colorectal, and liver cancers, and attention has been paid to the role of diet in the progression of these cancers. However, the relationship between dietary factors and cancers of the digestive system remains to be investigated.
Methods: This study included 30,789 adults aged 20 years or older from the National Health and Nutrition Examination Survey (NHANES), conducted from 2007 to 2018. It assessed the association between 30 dietary factors and digestive system cancers. Descriptive analysis was used to explore the demographic characteristics of the participants and p-values were calculated using a weighted linear regression model. Categorical variables were described as percentages, and p-values were calculated using weighted chi-square tests.
Results: We found that protein, vitamin B1, calcium, and iron intake were positively associated with colorectal cancer; vitamin B2 and phosphorus intake were negatively related to colorectal cancer; dietary folate and vitamin B12 intake were negatively associated with gastric cancer; vitamin D and copper intake were positively associated with gastric cancer; vitamin E intake was negatively related to the development of hepatocellular carcinoma; and lycopene, vitamin B2, calcium, iron, and zinc intake was positively associated with the development of liver cancer. Other than that, we did not observe any correlation between other dietary factors and cancers of the digestive system.
Conclusion: Dietary intake is associated with digestive system cancers, and more epidemiologic studies are needed to validate our results.

Keywords:  NHANES; colorectal cancer; dietary factors; gastric cancer; liver cancer; nutrients

DOI:  https://doi.org/10.3389/fnut.2025.1539401
J Pharmacol Exp Ther. 2025 Jan;pii: S0022-3565(24)00092-2. [Epub ahead of print]392(1): 100034

Metformin in overcoming enzalutamide resistance in castration-resistant prostate cancer.

Kendall Simpson, Derek B Allison, Daheng He, Jinpeng Liu, Chi Wang, Xiaoqi Liu.

  Androgen deprivation is the standard treatment for patients with prostate cancer. However, the disease eventually progresses as castration-resistant prostate cancer (CRPC). Enzalutamide, an androgen receptor inhibitor, is a typical drug for treating CRPC and with continuous reliance on the drug, can lead to enzalutamide resistance. This highlights the necessity for developing novel therapeutic targets to combat the gain of resistance. Metformin has been recently investigated for its potential antitumorigenic effects in many cancer types. In this study, we used enzalutamide and metformin in combination to explore the possible rescued efficacy of enzalutamide in the treatment of enzalutamide-resistant CRPC. We first tested the effects of this combination treatment on cell viability, drug synergy, and cell proliferation in enzalutamide-resistant CRPC cell lines. After combination treatment, we observed a decrease in cell proliferation and viability as well as a synergistic effect of both enzalutamide and metformin in vitro. Following these results, we sought to explore how combination treatment affected mitochondrial fitness using mitochondrial stress test analysis and mitochondrial membrane potential shifts due to metformin's action in inhibiting complex I of oxidative phosphorylation. We employed 2 different strategies for in vivo testing using 22Rv1 and LuCaP35CR xenograft models. Finally, RNA sequencing revealed a potential link in the downregulation of rat sarcoma-mitogen-activated protein kinase signaling following combination treatment. SIGNIFICANCE STATEMENT: Increasing evidence suggests that oxidative phosphorylation might play a critical role in the development of resistance to cancer therapy. This study showed that targeting oxidative phosphorylation with metformin can enhance the efficacy of enzalutamide in castration-resistant prostate cancer in vitro.

Keywords:  Enzalutamide resistance; Metformin; Prostate cancer

DOI:  https://doi.org/10.1124/jpet.124.002424
Neoplasia. 2025 Feb 03. pii: S1476-5586(25)00004-1. [Epub ahead of print]61 101125

SLC31A1 promotes chemoresistance through inducing CPT1A-mediated fatty acid oxidation in ER-positive breast cancer.

Xudong Li, Jingjing Ge, Mengdi Wan, Tongtong Feng, Xiaoqian Li, Haibo Zhang, Zhangyan Wang, Yongsheng Gao, Meiting Chen, Fei Pan.

  Over 60% of breast cancer cases are diagnosed with estrogen-receptor (ER) positive. Tamoxifen (TAM), a commonly employed medication for ER-positive breast cancer, often yields suboptimal therapeutic outcomes due to the emergence of TAM resistance, leading to the recurrence and a poor prognosis. The copper transporter, solute carrier family 31 member 1 (SLC31A1), has been associated with tumor aggressiveness and unfavorable outcomes in various types of tumors. In our current study, we found high expression of SLC31A1 that predicted poor survival in patients with breast cancer. Significantly, ER-positive breast cancer tissues in patients with recurrence post-TAM treatment exhibited considerably stronger SLC31A1 expression levels. In vitro experiments verified that TAM-resistant ER-positive breast cancer cell lines expressed notably higher SLC31A1 levels compared to the parental cell lines. Of great significance, SLC31A1 depletion notably rescued TAM sensitivity in chemoresistant ER-positive breast cancer cells, as demonstrated by the attenuated cell proliferative and invasive capabilities. Conversely, promoting SLC31A1 significantly facilitated the proliferation and invasion of wild-type breast cancer cells. Subsequently, we detected reduced copper levels in TAM-resistant breast cancer cells with SLC31A1 depletion. Mechanistically, we observed that in chemoresistant breast cancer cell lines, SLC31A1 knockdown resulted in a substantial decrease in the expression of carnitine palmitoyltransferase 1A (CPT1A), a rate-limiting enzyme of fatty acid oxidation (FAO). RNA-Seq analysis indicated that FAO might be implicated in SLC31A1-mediated breast cancer progression. CPT1A was also overexpressed in TAM-resistant breast cancer cells, accompanied by enhanced FAO rates and ATP levels. Suppressing CPT1A significantly enhanced the chemosensitivity of TAM-resistant breast cancer cells in response to TAM treatments. Intriguingly, copper exposure dose-dependently increased CPT1A expression in chemoresistant breast cancer cells, but this could be abolished upon SLC31A1 knockdown, along with enhanced apoptosis, which elucidated that copper uptake contributed to CPT1A expression. Furthermore, SLC31A1 overexpression significantly augmented CPT1A expression in parental breast cancer cells, accompanied by facilitated copper levels, FAO rates, and ATP levels, while being notably diminished upon CPT1A suppression. Finally, our in vivo studies confirmed that SLC31A1 deficiency re-sensitized TAM-resistant breast cancer cells to TAM treatment and abolished tumor growth. Collectively, all our studies demonstrated that SLC31A1/copper suppression could enhance TAM responses for chemoresistant ER-positive breast cancer cells through constraining the CPT1A-mediated FAO process.

Keywords:  CPT1A; ER-positive breast cancer; FAO; SLC31A1; Tamoxifen resistance

DOI:  https://doi.org/10.1016/j.neo.2025.101125
Pediatr Hematol Oncol. 2025 Jan 31. 1-20

Pediatric AML: state of the Art and Future Directions.

Prasad Iyer.

  Pediatric acute myeloid leukemia (AML) is a heterogeneous and aggressive hematological malignancy. Despite advances in treatment, the survival rates remain unsatisfactory, emphasizing the need for innovative therapeutic approaches. This narrative review presents a comprehensive overview of the current approach and likely future directions for pediatric AML. The distinct genetic, epigenetic, and molecular features of pediatric AML contribute to its complex pathophysiology and impact on prognosis. Current treatment practices involve a multifaceted approach combining chemotherapy, molecularly targeted therapies, and hematopoietic stem cell transplantation. However, intensive treatment often leads to significant acute and long-term toxicity. Emerging strategies, including precision medicine, immunotherapy, and novel agents, hold promise for improving outcomes and minimizing adverse effects. Ongoing clinical trials are investigating the potential of these innovative approaches to transform pediatric AML care. By highlighting the evolving treatment paradigms and future perspectives, this review underscores the importance of continued research and development in pediatric AML to enhance the survival rates and quality of life of these young patients.

Keywords:  Hematopoietic stem cell transplantation; immunotherapy; molecular diagnostics; pediatric acute myeloid leukemia; precision medicine; targeted therapies

DOI:  https://doi.org/10.1080/08880018.2025.2453861
Biochem Cell Biol. 2025 Feb 03.

Omega-3 polyunsaturated fatty acids modify glucose metabolism in THP-1 monocytes.

Michael Jae-Ho Byun, Roni Armon, Tamiris F G Souza, Hope D Anderson, Ayesha Saleem, Samantha Dawn Pauls.

Chronic inflammation is a driving factor in diseases like obesity and type 2 diabetes. Enhanced cellular glucose metabolism may contribute to heightened immune activation. A human supplementation trial showed that the n-3 PUFA α-linolenic acid (ALA) reduced oxidative phosphorylation in monocytes. Our objective here is to assess the direct effects of ALA and docosahexaenoic acid (DHA) on glucose metabolism in a cell culture model and to explore possible mechanisms. THP-1 monocytes were treated with 10-40 μM of ALA or DHA and compared with vehicle and oleic acid controls. The Seahorse XFe24 and Oroboros O2k Oxygraph systems were used to approximate catabolic rates in the presence of glucose. Both ALA and DHA reduced oxidative phosphorylation. We identified pyruvate dehydrogenase kinase 4 (PDK4) as a possible mechanistic candidate explaining the effect of DHA. Additionally, both n-3 PUFAs reduced LPS-induced IL-1β production, while only DHA increased reactive oxygen species to a small but significant extent. Our data suggest that ALA and DHA trigger a re-wiring of bioenergetic pathways in monocytes, possibly via the upregulation of PKD4. Given the close relationship between cell metabolism and immune cell activation, this may represent a novel mechanism by which n-3 PUFAs modulate immune function and inflammation.

DOI: https://doi.org/10.1139/bcb-2024-0202