bims-medica 2023-12-10 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2023‒12‒10
twenty-two papers selected by
Brett Chrest, East Carolina University

Probing human heart TCA cycle metabolism and response to glucose load using hyperpolarized [2-13 C]pyruvate MRS.
Role of monocarboxylate transporter I/lactate dehydrogenase B-mediated lactate recycling in tamoxifen-resistant breast cancer cells.
DMSA-coated IONPs trigger oxidative stress, mitochondrial metabolic reprograming and changes in mitochondrial disposition, hindering cell cycle progression of cancer cells.
RPLP2 activates TLR4 in an autocrine manner and promotes HIF-1α-induced metabolic reprogramming in hepatocellular carcinoma.
Systems levels analysis of lipid metabolism in oxygen-induced retinopathy.
ACOX1-mediated peroxisomal fatty acid oxidation contributes to metabolic reprogramming and survival in chronic lymphocytic leukemia.
Cancer-associated Fibroblasts in Neoadjuvant Setting for Solid Cancers.
Targeting the pyruvate dehydrogenase complex/pyruvate dehydrogenase kinase (PDC/PDK) axis to discover potent PDK inhibitors through structure-based virtual screening and pharmacological evaluation.
The effect of a ketogenic diet on weight loss in CKD: a randomized controlled trial in obese stage G1-3a CKD patients.
Functional and spatial proteomics profiling reveals intra- and intercellular signaling crosstalk in colorectal cancer.
Tetraarsenic tetrasulfide triggers ROS-induced apoptosis and ferroptosis in B-cell acute lymphoblastic leukaemia by targeting HK2.
Hyperpolarized 13 C Metabolic MRI of Patients with Pancreatic Ductal Adenocarcinoma.
Mitocurcumin utilizes oxidative stress to upregulate JNK/p38 signaling and overcomes Cytarabine resistance in acute myeloid leukemia.
An imidazo[1,2-a]pyridine-pyridine derivative potently inhibits FLT3-ITD and FLT3-ITD secondary mutants, including gilteritinib-resistant FLT3-ITD/F691L.
ACAT1 deficiency in myeloid cells promotes glioblastoma progression by enhancing the accumulation of myeloid-derived suppressor cells.
Pyruvate metabolism regulates prostate cell fate and response to cancer therapy.
Collective mitochondrial dynamics resolve conflicting cellular tensions: From plants to general principles.
Redox and detox: Malate shuttle metabolism keeps exhausted T cells fit.
The mitochondrial fission protein DRP1 influences memory CD8+ T cell formation and function.
Checkmate: Metabolic flexibility with a STING in its tail.
Cancer Evolution: A Multifaceted Affair.
Disclosing a metabolic signature of cisplatin resistance in MDA-MB-231 triple-negative breast cancer cells by NMR metabolomics.

NMR Biomed. 2023 Dec 06. e5074

Probing human heart TCA cycle metabolism and response to glucose load using hyperpolarized [2-13 C]pyruvate MRS.

Hsin-Yu Chen, Jeremy W Gordon, Nicholas Dwork, Brian T Chung, Andrew Riselli, Sanjay Sivalokanathan, Robert A Bok, James B Slater, Daniel B Vigneron, M Roselle Abraham, Peder E Z Larson.

  INTRODUCTION: The healthy heart has remarkable metabolic flexibility that permits rapid switching between mitochondrial glucose oxidation and fatty acid oxidation to generate ATP. Loss of metabolic flexibility has been implicated in the genesis of contractile dysfunction seen in cardiomyopathy. Metabolic flexibility has been imaged in experimental models, using hyperpolarized (HP) [2-13 C]pyruvate MRI, which enables interrogation of metabolites that reflect tricarboxylic acid (TCA) cycle flux in cardiac myocytes. This study aimed to develop methods, demonstrate feasibility for [2-13 C]pyruvate MRI in the human heart for the first time, and assess cardiac metabolic flexibility.METHODS: Good manufacturing practice [2-13 C]pyruvic acid was polarized in a 5 T polarizer for 2.5-3 h. Following dissolution, quality control parameters of HP pyruvate met all safety and sterility criteria for pharmacy release, prior to administration to study subjects. Three healthy subjects each received two HP injections and MR scans, first under fasting conditions, followed by oral glucose load. A 5 cm axial slab-selective spectroscopy approach was prescribed over the left ventricle and acquired at 3 s intervals on a 3 T clinical MRI scanner.
RESULTS: The study protocol, which included HP substrate injection, MR scanning, and oral glucose load, was performed safely without adverse events. Key downstream metabolites of [2-13 C]pyruvate metabolism in cardiac myocytes include the glycolytic derivative [2-13 C]lactate, TCA-associated metabolite [5-13 C]glutamate, and [1-13 C]acetylcarnitine, catalyzed by carnitine acetyltransferase (CAT). After glucose load, 13 C-labeling of lactate, glutamate, and acetylcarnitine from 13 C-pyruvate increased by an average of 39.3%, 29.5%, and 114% respectively in the three subjects, which could result from increases in lactate dehydrogenase, pyruvate dehydrogenase, and CAT enzyme activity as well as TCA cycle flux (glucose oxidation).
CONCLUSIONS: HP [2-13 C]pyruvate imaging is safe and permits noninvasive assessment of TCA cycle intermediates and the acetyl buffer, acetylcarnitine, which is not possible using HP [1-13 C]pyruvate. Cardiac metabolite measurement in the fasting/fed states provides information on cardiac metabolic flexibility and the acetylcarnitine pool.

Keywords:  TCA cycle; hyperpolarized 13C MRS; metabolism; oral glucose load test; pyruvate

DOI:  https://doi.org/10.1002/nbm.5074
Arch Pharm Res. 2023 Dec 04.

Role of monocarboxylate transporter I/lactate dehydrogenase B-mediated lactate recycling in tamoxifen-resistant breast cancer cells.

Min Chang Choi, Sang Kyum Kim, Young Jae Choi, Yong June Choi, Suntae Kim, Kyung Hwan Jegal, Sung Chul Lim, Keon Wook Kang.

  Although tamoxifen (TAM) is widely used in patients with estrogen receptor-positive breast cancer, the development of tamoxifen resistance is common. The previous finding suggests that the development of tamoxifen resistance is driven by epiregulin or hypoxia-inducible factor-1α-dependent glycolysis activation. Nonetheless, the mechanisms responsible for cancer cell survival and growth in a lactic acid-rich environment remain elusive. We found that the growth and survival of tamoxifen-resistant MCF-7 cells (TAMR-MCF-7) depend on glycolysis rather than oxidative phosphorylation. The levels of the glycolytic enzymes were higher in TAMR-MCF-7 cells than in parental MCF-7 cells, whereas the mitochondrial number and complex I level were decreased. Importantly, TAMR-MCF-7 cells were more resistant to low glucose and high lactate growth conditions. Isotope tracing analysis using 13C-lactate confirmed that lactate conversion to pyruvate was enhanced in TAMR-MCF-7 cells. We identified monocarboxylate transporter1 (MCT1) and lactate dehydrogenase B (LDHB) as important mediators of lactate influx and its conversion to pyruvate, respectively. Consistently, AR-C155858 (MCT1 inhibitor) inhibited the proliferation, migration, spheroid formation, and in vivo tumor growth of TAMR-MCF-7 cells. Our findings suggest that TAMR-MCF-7 cells depend on glycolysis and glutaminolysis for energy and support that targeting MCT1- and LDHB-dependent lactate recycling may be a promising strategy to treat patients with TAM-resistant breast cancer.

Keywords:  Glutamine; Glycolysis; Lactate; MCT1; Tamoxifen resistance

DOI:  https://doi.org/10.1007/s12272-023-01474-x
Biomaterials. 2023 Nov 29. pii: S0142-9612(23)00417-9. [Epub ahead of print]304 122409

DMSA-coated IONPs trigger oxidative stress, mitochondrial metabolic reprograming and changes in mitochondrial disposition, hindering cell cycle progression of cancer cells.

Neus Daviu, Yadileiny Portilla, Marta Gómez de Cedrón, Ana Ramírez de Molina, Domingo F Barber.

  There is increasing interest in modulating the redox homeostasis of tumors since high levels of reactive oxygen species (ROS) make them more vulnerable to changes in these species. Nanomedicine offers promise in this context as such applications may provoke biological responses that induce ROS production. Indeed, iron oxide nanoparticles (IONPs) can induce ROS accumulation through the so-called Fenton reaction of iron, further augmenting the ROS in tumors and overloading the antioxidant system beyond its capacity, thereby driving oxidative stress to a level that is incompatible with cell survival. Here, three different coatings for IONPs were compared to assess their intrinsic capacity to induce ROS production in cells. Of these coatings, dimercaptosuccinic acid-coated IONPs (DMSA-NPs) provoked the strongest ROS production, which was associated with the ability to reprogram the metabolism of cancer cells. This latter phenomenon involved shutting-down oxidative phosphorylation (OXPHOS), shifting mitochondrial morphology towards a more elongated phenotype, reducing the total mitochondrial mass and ultimately, blocking cell proliferation by inducing G0/G1 cell cycle arrest. Consequently, the data obtained highlights the importance of studying the chemical properties of IONPs, presenting DMSA-NPs as a novel tool to induce oxidative stress in cancer cells and alter their cell fate.

Keywords:  Iron oxide nanoparticles; Metabolic reprogramming; Mitochondrial dynamics and cell proliferation; Oxidative stress

DOI:  https://doi.org/10.1016/j.biomaterials.2023.122409
Cell Death Discov. 2023 Dec 05. 9(1): 440

RPLP2 activates TLR4 in an autocrine manner and promotes HIF-1α-induced metabolic reprogramming in hepatocellular carcinoma.

Qingqing Yang, Xiangrui Meng, Jin Chen, Xiangsu Li, Yang Huang, Xueyi Xiao, Rongqing Li, Xudong Wu.

Metabolic reprogramming is a major feature of cancer, and aerobic glycolysis is one of the most widely studied metabolic reprogramming processes. Acidic ribosome protein P2 (RPLP2) is associated with both tumorigenesis and endoplasmic reticulum stress. However, limited knowledge exists regarding the role of RPLP2 in hepatocellular carcinoma (HCC) progression. In the present study, we observed a significant upregulation of RPLP2 in HCC tissues. Moreover, RPLP2 expression is closely correlated with patient prognosis and survival. The subsequent experimental validation demonstrated that RPLP2 exerted a regulatory effect on the expression of glycolytic enzymes and lactate production, thereby facilitating HCC cell proliferation. Mechanistically, the PI3K/AKT signalling pathway was found to play an important role in the regulation of hypoxia-inducible factor-1α (HIF-1α)-mediated aerobic glycolysis and cell growth. RPLP2 activates TLR4 on the surface of HCC cells and the downstream PI3K/AKT pathway through autocrine signalling. This activation then facilitates the entry of HIF-1α into the nucleus, enabling it to fulfil its transcriptional function. In conclusion, our findings suggested that RPLP2 induces a metabolic shift towards aerobic glycolysis and facilitates the progression of HCC through TLR4-dependent activation of the PI3K/AKT/HIF-1α pathway. Our study revealed the novel mechanism by which the ribosomal protein RPLP2 regulates glycolysis to promote HCC progression. These findings may offer a potential therapeutic target for HCC treatment.

DOI: https://doi.org/10.1038/s41420-023-01719-0
bioRxiv. 2023 Nov 30. pii: 2023.11.21.568200. [Epub ahead of print]

Systems levels analysis of lipid metabolism in oxygen-induced retinopathy.

Charandeep Singh.

Hyperoxia induces glutamine-fueled anaplerosis in the Muller cells, endothelial cells, and retinal explants. Anaplerosis takes away glutamine from the biosynthetic pathway to the energy-producing TCA cycle. This process depletes biosynthetic precursors from newly proliferating endothelial cells. The induction of anaplerosis in the hyperoxic retina is a compensatory response, either to decreased glycolysis or decreased flux from glycolysis to the TCA cycle. We hypothesized that by providing substrates that feed into TCA, we could reverse or prevent glutamine-fueled anaplerosis, thereby abating the glutamine wastage for energy generation. Using an oxygen-induced retinopathy (OIR) mouse model, we first compared the difference in fatty acid metabolism between OIR-resistant BALB/cByJ and OIR susceptible C57BL/6J strains to understand if these strains exhibit metabolic difference that protects BALB/cByJ from the hyperoxic conditions and prevents their vasculature in oxygen-induced retinopathy model. Based on our findings from the metabolic comparison between two mouse strains, we hypothesized that the medium-chain fatty acid, octanoate, can feed into the TCA and serve as an alternative energy source in response to hyperoxia. Our systems levels analysis of OIR model shows that the medium chain fatty acid can serve as an alternative source to feed TCA. We here, for the first time, demonstrate that the retina can use medium-chain fatty acid octanoate to replenish TCA in normoxic and at a higher rate in hyperoxic conditions.

DOI: https://doi.org/10.1101/2023.11.21.568200
Leukemia. 2023 Dec 06.

ACOX1-mediated peroxisomal fatty acid oxidation contributes to metabolic reprogramming and survival in chronic lymphocytic leukemia.

Mariana Tannoury, Marianne Ayoub, Léa Dehgane, Ivan Nemazanyy, Kenza Dubois, Charlotte Izabelle, Aurélie Brousse, Damien Roos-Weil, Karim Maloum, Hélène Merle-Béral, Brigitte Bauvois, Bruno Saubamea, Elise Chapiro, Florence Nguyen-Khac, Delphine Garnier, Santos A Susin.

Chronic lymphocytic leukemia (CLL) is still an incurable disease, with many patients developing resistance to conventional and targeted therapies. To better understand the physiology of CLL and facilitate the development of innovative treatment options, we examined specific metabolic features in the tumor CLL B-lymphocytes. We observed metabolic reprogramming, characterized by a high level of mitochondrial oxidative phosphorylation activity, a low glycolytic rate, and the presence of C2- to C6-carnitine end-products revealing an unexpected, essential role for peroxisomal fatty acid beta-oxidation (pFAO). Accordingly, downmodulation of ACOX1 (a rate-limiting pFAO enzyme overexpressed in CLL cells) was enough to shift the CLL cells' metabolism from lipids to a carbon- and amino-acid-based phenotype. Complete blockade of ACOX1 resulted in lipid droplet accumulation and caspase-dependent death in CLL cells, including those from individuals with poor cytogenetic and clinical prognostic factors. In a therapeutic translational approach, ACOX1 inhibition spared non-tumor blood cells from CLL patients but led to the death of circulating, BCR-stimulated CLL B-lymphocytes and CLL B-cells receiving pro-survival stromal signals. Furthermore, a combination of ACOX1 and BTK inhibitors had a synergistic killing effect. Overall, our results highlight a less-studied but essential metabolic pathway in CLL and pave the way towards the development of new, metabolism-based treatment options.

DOI: https://doi.org/10.1038/s41375-023-02103-8
Crit Rev Oncol Hematol. 2023 Dec 04. pii: S1040-8428(23)00314-1. [Epub ahead of print] 104226

Cancer-associated Fibroblasts in Neoadjuvant Setting for Solid Cancers.

Yanan Gu, Qiangda Chen, Hanlin Yin, Mengsu Zeng, Shanshan Gao, Xiaolin Wang.

  Therapeutic approaches for cancer have become increasingly diverse in recent times. A comprehensive understanding of the tumor microenvironment (TME) holds great potential for enhancing the precision of tumor therapies. Neoadjuvant therapy offers the possibility of alleviating patient symptoms and improving overall quality of life. Additionally, it may facilitate the reduction of inoperable tumors and prevent potential preoperative micrometastases. Within the TME, cancer-associated fibroblasts (CAFs) play a prominent role as they generate various elements that contribute to tumor progression. Particularly, extracellular matrix (ECM) produced by CAFs prevents immune cell infiltration into the TME, hampers drug penetration, and diminishes therapeutic efficacy. Therefore, this review provides a summary of the heterogeneity and interactions of CAFs within the TME, with a specific focus on the influence of neoadjuvant therapy on the microenvironment, particularly CAFs. Finally, we propose several potential and promising therapeutic strategies targeting CAFs, which may efficiently eliminate CAFs to decrease stroma density and impair their functions.

Keywords:  cancer-associated fibroblasts; chemotherapy; immunotherapy; neoadjuvant therapy; radiotherapy; solid cancer; targeted therapy

DOI:  https://doi.org/10.1016/j.critrevonc.2023.104226
Eur J Med Chem. 2023 Dec 03. pii: S0223-5234(23)00975-3. [Epub ahead of print]264 116008

Targeting the pyruvate dehydrogenase complex/pyruvate dehydrogenase kinase (PDC/PDK) axis to discover potent PDK inhibitors through structure-based virtual screening and pharmacological evaluation.

Linling Gan, Ying Yang, Zizhen Liang, Maojie Zhang, Yun He, Shao-Lin Zhang.

  Proliferating cancer cells are characterized by the Warburg effect, a metabolic alteration in which ATP is generated from cytoplasmic glycolysis instead of oxidative phosphorylation. The pyruvate dehydrogenase complex/pyruvate dehydrogenase kinase (PDC/PDK) axis plays a crucial role in this effect and has been identified as a potential target for anticancer drug development. Herein, we present the discovery and pharmacological evaluation of potent PDK inhibitors targeting the PDK/PDC axis. We successfully identified 6 compounds from a small molecule library through a structure-based virtual screening campaign and evaluated their enzymatic inhibitory potencies for PDK1-4. Our results indicated that compound 1 exhibited submicromolar inhibitory activities against PDK1-3 (IC50 = 109.3, 135.8, and 458.7 nM, respectively), but is insensitive to PDK4 (IC50 = 8.67 μM). Furthermore, compound 1 inhibited the proliferation of A549 cells with an EC50 value of 10.7 μM. In addition, compound 1 induced cell apoptosis, arrested the cell cycle at the S phase, and reduced cell invasion and migration, while showing low in vivo toxicity at a high dose. Based on these observations, it can be concluded that compound 1 is a promising anti-PDK1-3 lead that merits further investigation.

Keywords:  Anticancer; Cancer metabolism; Pyruvate dehydrogenase kinase

DOI:  https://doi.org/10.1016/j.ejmech.2023.116008
Clin Kidney J. 2023 Dec;16(12): 2309-2313

The effect of a ketogenic diet on weight loss in CKD: a randomized controlled trial in obese stage G1-3a CKD patients.

Carmine Zoccali, Vincenzo Bellizzi, Roberto Minutolo, Francesca Mallamaci, Giuseppe Conte, Luca De Nicola.

  This study describes a multicentre randomized controlled trial comparing the effects of a ketogenic diet with a low-energy standard diet containing 0.8 g/kg/day on weight loss and metabolic alterations in adult patients with mild-to-moderate non-diabetic chronic kidney disease (CKD) and mild-to-severe obesity. The study is being conducted to understand the impact of the ketogenic diet on weight loss in these patients, as the existing evidence on the ketogenic diet's effect in CKD patients is limited and inconclusive. The study will enrol mild-to moderate adult CKD patients (Stages G1-3a) with albumin to creatinine ratio ≥200 mg/g, without diabetes, with obesity (body mass index ≥30 kg/m2), and stable body weight and estimated glomerular filtration rate from at least 3 months. The primary outcome will be weight loss at 6 months, and secondary outcomes will include adherence to prescribed dietary regimens, body composition changes, changes in standardized blood pressure measurements, metabolic parameters, lipid profile, liver profile, mineral bone disease biomarkers, and changes in renal function and albuminuria. The findings of this study will contribute to a better understanding of the potential benefits and risks of the ketogenic diet in CKD patients with obesity. The results will help guide future research on the ketogenic diet and renal health.

Keywords:  CKD; dietary proteins; ketogenic diet; low-carbohydrate diet; obesity

DOI:  https://doi.org/10.1093/ckj/sfad176
iScience. 2023 Dec 15. 26(12): 108399

Functional and spatial proteomics profiling reveals intra- and intercellular signaling crosstalk in colorectal cancer.

Christina Plattner, Giorgia Lamberti, Peter Blattmann, Alexander Kirchmair, Dietmar Rieder, Zuzana Loncova, Gregor Sturm, Stefan Scheidl, Marieke Ijsselsteijn, Georgios Fotakis, Asma Noureen, Rebecca Lisandrelli, Nina Böck, Niloofar Nemati, Anne Krogsdam, Sophia Daum, Francesca Finotello, Antonios Somarakis, Alexander Schäfer, Doris Wilflingseder, Miguel Gonzalez Acera, Dietmar Öfner, Lukas A Huber, Hans Clevers, Christoph Becker, Henner F Farin, Florian R Greten, Ruedi Aebersold, Noel F C C de Miranda, Zlatko Trajanoski.

  Precision oncology approaches for patients with colorectal cancer (CRC) continue to lag behind other solid cancers. Functional precision oncology-a strategy that is based on perturbing primary tumor cells from cancer patients-could provide a road forward to personalize treatment. We extend this paradigm to measuring proteome activity landscapes by acquiring quantitative phosphoproteomic data from patient-derived organoids (PDOs). We show that kinase inhibitors induce inhibitor- and patient-specific off-target effects and pathway crosstalk. Reconstruction of the kinase networks revealed that the signaling rewiring is modestly affected by mutations. We show non-genetic heterogeneity of the PDOs and upregulation of stemness and differentiation genes by kinase inhibitors. Using imaging mass-cytometry-based profiling of the primary tumors, we characterize the tumor microenvironment (TME) and determine spatial heterocellular crosstalk and tumor-immune cell interactions. Collectively, we provide a framework for inferring tumor cell intrinsic signaling and external signaling from the TME to inform precision (immuno-) oncology in CRC.

Keywords:  Cancer; Cancer systems biology; Proteomics

DOI:  https://doi.org/10.1016/j.isci.2023.108399
Transl Oncol. 2023 Dec 02. pii: S1936-5233(23)00236-X. [Epub ahead of print]40 101850

Tetraarsenic tetrasulfide triggers ROS-induced apoptosis and ferroptosis in B-cell acute lymphoblastic leukaemia by targeting HK2.

Wenke Bai, Diandian Liu, Qianyi Cheng, Xingge Yang, Liwen Zhu, Lijun Qin, Jianpei Fang.

  PURPOSE: Acute lymphoblastic leukemia (ALL) is the most common type of cancer diagnosed in children. Despite cure rates of higher than 85 %, refractory or relapsed ALL still exhibits a bleak prognosis indicative of the dearth of treatment modalities specific for relapsed or refractory ALL. Prior research has implicated metabolic alterations in leukemia pathogenesis, and literature on the therapeutic efficacy of arsenic compounds targeting metabolic pathways in B-cell acute lymphoblastic leukemia (B-ALL) cells is scarce.METHODS: A compound extracted from realgar, tetraarsenic tetrasulfide (As4S4), and its antitumor effects on B-ALL were experimentally examined in vitro and in vivo.
RESULTS: As4S4 apparently targets B-ALL cells by inducing specific cellular responses, including apoptosis, G2/M arrest, and ferroptosis. Interestingly, these effects are attributed to reactive oxygen species (ROS) accumulation, and increased ROS levels have been linked to both the mitochondria-dependent caspase cascade and the activation of p53 signaling. The ROS scavenger N-acetylcysteine (NAC) can counteract the effects of As4S4 treatment on Nalm-6 and RS4;11 cells. Specifically, by targeting Hexokinase-2 (HK2), As4S4 induces alterations in mitochondrial membrane potential and disrupts glucose metabolism, leading to ROS accumulation, and was shown to inhibit B-ALL cell proliferation in vitro and in vivo. Intriguingly, overexpression of HK2 can partially desensitize B-ALL cells to As4S4 treatment.
CONCLUSION: Tetraarsenic tetrasulfide can regulate the Warburg effect by controlling HK2 expression, a finding that provides both new mechanistic insight into metabolic alterations and pharmacological evidence for the clinical treatment of B-ALL.

Keywords:  B-ALL; Ferroptosis; Hexokinases2; ROS; Tetraarsenic tetrasulfide

DOI:  https://doi.org/10.1016/j.tranon.2023.101850
J Magn Reson Imaging. 2023 Dec 02.

Hyperpolarized 13 C Metabolic MRI of Patients with Pancreatic Ductal Adenocarcinoma.

Jeremy W Gordon, Hsin-Yu Chen, Tanner Nickles, Philip M Lee, Robert Bok, Michael A Ohliger, Kimberly Okamoto, Andrew H Ko, Peder E Z Larson, Zhen J Wang.

  BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related death in the United States. However, early response assessment using the current approach of measuring changes in tumor size on computed tomography (CT) or MRI is challenging.PURPOSE: To investigate the feasibility of hyperpolarized (HP) [1-13 C]pyruvate MRI to quantify metabolism in the normal appearing pancreas and PDA, and to assess changes in PDA metabolism following systemic chemotherapy.
STUDY TYPE: Prospective.
SUBJECTS: Six patients (65.0 ± 7.6 years, 2 females) with locally advanced or metastatic PDA enrolled prior to starting a new line of systemic chemotherapy.
FIELD STRENGTH/SEQUENCE: 3-T, T1-weighted gradient echo, metabolite-selective 13 C echoplanar imaging.
ASSESSMENT: Time-resolved HP [1-13 C]pyruvate data were acquired before (N = 6) and 4-weeks after (N = 3) treatment initiation. Pyruvate metabolism, as quantified by pharmacokinetic modeling and metabolite area-under-the-curve ratios, was assessed in manually segmented PDA and normal appearing pancreas ROIs (N = 5). The change in tumor metabolism before and 4-weeks after treatment initiation was assessed in primary PDA (N = 2) and liver metastases (N = 1), and was compared to objective tumor response defined by response evaluation criteria in solid tumors (RECIST) on subsequent CTs.
STATISTICAL TESTS: Descriptive tests (mean ± standard deviation), model fit error for pharmacokinetic rate constants.
RESULTS: Primary PDA showed reduced alanine-to-lactate ratios when compared to normal pancreas, due to increased lactate-to-pyruvate or reduced alanine-to-pyruvate ratios. Of the three patients who received HP [1-13 C]pyruvate MRI before and 4-weeks after treatment initiation, one patient had a primary tumor with early metabolic response (increase in alanine-to-lactate) and subsequent partial response according to RECIST, one patient had a primary tumor with relatively stable metabolism and subsequent stable disease by RECIST, and one patient had metastatic PDA with increase in lactate-to-pyruvate of the liver metastases and corresponding progressive disease according to RECIST.
DATA CONCLUSION: Altered pyruvate metabolism with increased lactate or reduced alanine was observed in the primary tumor. Early metabolic response assessed at 4-weeks after treatment initiation correlated with subsequent objective tumor response assessed using RECIST.
LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Keywords:  carbon-13; hyperpolarization; pancreas; pancreatic cancer; pancreatic ductal adenocarcinoma; pyruvate

DOI:  https://doi.org/10.1002/jmri.29162
Cell Signal. 2023 Dec 02. pii: S0898-6568(23)00419-9. [Epub ahead of print] 111004

Mitocurcumin utilizes oxidative stress to upregulate JNK/p38 signaling and overcomes Cytarabine resistance in acute myeloid leukemia.

Tarang Gaur, Ahlam Ali, Deepak Sharma, Saurabh Kumar Gupta, Vikram Gota, Bhausaheb Bagal, Uwe Platzbeckar, Rohit Mishra, Amit Dutt, Navin Khattry, Ken Mills, Md Imtaiyaz Hassan, Santosh Sandur, Syed K Hasan.

  Acute myeloid leukemia (AML) is a type of blood cancer that is characterized by the rapid growth of abnormal myeloid cells. The goal of AML treatment is to eliminate the leukemic blasts, which is accomplished through intensive chemotherapy. Cytarabine is a key component of the standard induction chemotherapy regimen for AML. However, despite a high remission rate, 70-80% of AML patients relapse and develop resistance to Cytarabine, leading to poor clinical outcomes. Mitocurcumin (MitoC), a derivative of curcumin that enters mitochondria, leading to a drop in mitochondrial membrane potential and mitophagy induction. Further, it activates oxidative stress-mediated JNK/p38 signaling to induce apoptosis. MitoC demonstrated a preferential ability to kill leukemic cells from AML cell lines and patient-derived leukemic blasts. RNA sequencing data suggests perturbation of DNA damage response and cell proliferation pathways in MitoC-treated AML. Elevated reactive oxygen species (ROS) in MitoC-treated AML cells resulted in significant DNA damage and cell cycle arrest. Further, MitoC treatment resulted in ROS-mediated enhanced levels of p21, which leads to suppression of CHK1, RAD51, Cyclin-D and c-Myc oncoproteins, potentially contributing to cytarabine resistance. Combinatorial treatment of MitoC and Cytarabine has shown synergism, increased apoptosis, and enhanced DNA damage. Using AML xenografts, a significant reduction of hCD45+ cells was observed in AML mice bone marrow treated with MitoC (mean 0.6%; range0.04%-3.56%) compared to control (mean 38.2%; range10.1%-78%), p = 0.03. The data suggest that MitoC exploits stress-induced leukemic oxidative environment to up-regulate JNK/p38 signaling to lead to apoptosis and can potentially overcome cytarabine resistance via ROS/p21/CHK1 axis.

Keywords:  Acute myeloid leukemia; Cytarabine resistance; JNK; Mitocurcumin; Oxidative stress

DOI:  https://doi.org/10.1016/j.cellsig.2023.111004
Eur J Med Chem. 2023 Nov 25. pii: S0223-5234(23)00944-3. [Epub ahead of print]264 115977

An imidazo[1,2-a]pyridine-pyridine derivative potently inhibits FLT3-ITD and FLT3-ITD secondary mutants, including gilteritinib-resistant FLT3-ITD/F691L.

Xiuqi Wang, Rosa Anna DeFilippis, Tsigereda Weldemichael, Naresh Gunaganti, Phuc Tran, Yuet-Kin Leung, Neil P Shah, Hong-Yu Li.

  FLT3 activating mutations are detected in approximately 30 % of newly diagnosed acute myeloid leukemia (AML) cases, most commonly consisting of internal tandem duplication (ITD) mutations in the juxtamembrane region. Recently, several FLT3 inhibitors have demonstrated clinical activity and three are currently approved - midostaurin, quizartinib, and gilteritinib. Midostaurin is a first-generation FLT3 inhibitor with minimal activity as monotherapy. Midostaurin lacks selectivity and is only approved by the USFDA for use in combination with other chemotherapy agents. The second-generation inhibitors quizartinib and gilteritinib display improved specificity and selectivity, and have been approved for use as monotherapy. However, their clinical efficacies are limited in part due to the emergence of drug-resistant FLT3 secondary mutations in the tyrosine kinase domain at positions D835 and F691. Therefore, in order to overcome drug resistance and further improve outcomes, new compounds targeting FLT3-ITD with secondary mutants are urgently needed. In this study, through the structural modification of a reported compound Ling-5e, we identified compound 24 as a FLT3 inhibitor that is equally potent against FLT3-ITD and the clinically relevant mutants FLT3-ITD/D835Y, and FLT3-ITD/F691L. Its inhibitory effects were demonstrated in both cell viability assays and western blots analyses. When tested against cell lines lacking activating mutations in FLT3, no non-specific cytotoxicity effect was observed. Interestingly, molecular docking results showed that compound 24 may adopt different binding conformations with FLT3-F691L compared to FLT3, which may explain its retained activity against FLT3-ITD/F691L. In summary, compound 24 has inhibition potency on FLT3 comparable to gilteritinib, but a more balanced inhibition on FLT3 secondary mutations, especially FLT3-ITD/F691L which is gilteritinib resistant. Compound 24 may serve as a promising lead for the drug development of either primary or relapsed AML with FLT3 secondary mutations.

Keywords:  AML; Cancer; FLT3-ITD; Mutation

DOI:  https://doi.org/10.1016/j.ejmech.2023.115977
Acta Pharm Sin B. 2023 Dec;13(12): 4733-4747

ACAT1 deficiency in myeloid cells promotes glioblastoma progression by enhancing the accumulation of myeloid-derived suppressor cells.

Mingjin Wang, Weida Wang, Shen You, Zhenyan Hou, Ming Ji, Nina Xue, Tingting Du, Xiaoguang Chen, Jing Jin.

  Glioblastoma (GBM) is a highly aggressive and lethal brain tumor with an immunosuppressive tumor microenvironment (TME). In this environment, myeloid cells, such as myeloid-derived suppressor cells (MDSCs), play a pivotal role in suppressing antitumor immunity. Lipometabolism is closely related to the function of myeloid cells. Here, our study reports that acetyl-CoA acetyltransferase 1 (ACAT1), the key enzyme of fatty acid oxidation (FAO) and ketogenesis, is significantly downregulated in the MDSCs infiltrated in GBM patients. To investigate the effects of ACAT1 on myeloid cells, we generated mice with myeloid-specific (LyzM-cre) depletion of ACAT1. The results show that these mice exhibited a remarkable accumulation of MDSCs and increased tumor progression both ectopically and orthotopically. The mechanism behind this effect is elevated secretion of C-X-C motif ligand 1 (CXCL1) of macrophages (Mφ). Overall, our findings demonstrate that ACAT1 could serve as a promising drug target for GBM by regulating the function of MDSCs in the TME.

Keywords:  Acetyl-CoA acetyltransferase 1; CXCL1; Glioblastoma; Lipid metabolism; Macrophages; Myeloid cells; Myeloid-derived suppressor cells; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.apsb.2023.09.005
Nat Cell Biol. 2023 Dec 04.

Pyruvate metabolism regulates prostate cell fate and response to cancer therapy.

DOI: https://doi.org/10.1038/s41556-023-01290-x
Semin Cell Dev Biol. 2024 Mar 15. pii: S1084-9521(23)00169-6. [Epub ahead of print]156 253-265

Collective mitochondrial dynamics resolve conflicting cellular tensions: From plants to general principles.

Joanna M Chustecki, Iain G Johnston.

  Mitochondria play diverse and essential roles in eukaryotic cells, and plants are no exception. Plant mitochondria have several differences from their metazoan and fungal cousins: they often exist in a fragmented state, move rapidly on actin rather than microtubules, have many plant-specific metabolic features and roles, and usually contain only a subset of the complete mtDNA genome, which itself undergoes frequent recombination. This arrangement means that exchange and complementation is essential for plant mitochondria, and recent work has begun to reveal how their collective dynamics and resultant "social networks" of encounters support this exchange, connecting plant mitochondria in time rather than in space. This review will argue that this social network perspective can be extended to a "societal network", where mitochondrial dynamics are an essential part of the interacting cellular society of organelles and biomolecules. Evidence is emerging that mitochondrial dynamics allow optimal resolutions to competing cellular priorities; we will survey this evidence and review potential future research directions, highlighting that plant mitochondria can help reveal and test principles that apply across other kingdoms of life. In parallel with this fundamental cell biology, we also highlight the translational "One Health" importance of plant mitochondrial behaviour - which is exploited in the production of a vast amount of crops consumed worldwide - and the potential for multi-objective optimisation to understand and rationally re-engineer the evolved resolutions to these tensions.

Keywords:  MtDNA inheritance; MtDNA maintenance; Multi-objective optimisation; Plant mitochondrial dynamics; Social network

DOI:  https://doi.org/10.1016/j.semcdb.2023.09.005
Cell Metab. 2023 Dec 05. pii: S1550-4131(23)00416-3. [Epub ahead of print]35(12): 2101-2103

Redox and detox: Malate shuttle metabolism keeps exhausted T cells fit.

Alok Kumar, Greg M Delgoffe.

The malate shuttle is known to maintain the balance of NAD+/NADH between the cytosol and mitochondria. However, in Tex cells, it primarily detoxifies ammonia (via GOT1-mediated production of 2-KG in an atypical reaction) and provides longevity to chronic-infection-induced Tex cells against ammonia-induced cell death.

DOI: https://doi.org/10.1016/j.cmet.2023.11.005
J Leukoc Biol. 2023 Dec 06. pii: qiad155. [Epub ahead of print]

The mitochondrial fission protein DRP1 influences memory CD8+ T cell formation and function.

Marissa G Stevens, Frank M Mason, Timothy N J Bullock.

  Pharmacological methods for promoting mitochondrial elongation suggest that effector T cells can be altered to support a memory T cell-like metabolic state. Such mitochondrial elongation approaches may enhance the development of immunological memory. Therefore, we hypothesized that deletion of the mitochondrial fission protein, DRP1, would lead to mitochondrial elongation and generate a large memory T cell population, an approach that could be exploited to enhance vaccination protocols. We find that, as expected, while deletion of DRP1 from T cells in dLckCre x Drp1flfl does compromise the magnitude and functionality of primary effector CD8+ T cells, a disproportionately large pool of memory CD8+ T cells does form. In contrast to primary effector CD8+ T cells, DRP1-deficient memory dLckCre x Drp1flfl CD8+ T cells mount a secondary response comparable to control memory T cells with respect to kinetics, magnitude, and effector capabilities. Interestingly, the relative propensity to form memory cells in the absence of DRP1 was neither associated with differentiation toward more memory precursor CD8+ T cells nor decreased cellular death of effector T cells. Instead, the tendency to form memory CD8+ T cells in the absence of DRP1 is associated with decreased TCR expression. Remarkably, in a competitive environment with DRP1-replete CD8+ T cells, the absence of DRP1 from CD8+ T cells compromised the generation of primary, memory and secondary responses, indicating that approaches targeting DRP1 need to be carefully tailored.

Keywords:  CD8+ T cell; Cell Death; Cytokine; Differentiation; Memory T cell; Metabolism; Mitochondria; T cell receptor

DOI:  https://doi.org/10.1093/jleuko/qiad155
Sci Adv. 2023 Dec 08. 9(49): eadm6816

Checkmate: Metabolic flexibility with a STING in its tail.

Roddy S O'Connor.

Inhibiting a key metabolic enzyme, ACLY, in cancer cells impacts T cell function in immunotherapy-resistant tumors and may offer a target for therapeutic treatment.

DOI: https://doi.org/10.1126/sciadv.adm6816
Cancer Discov. 2023 Dec 06. OF1-OF13

Cancer Evolution: A Multifaceted Affair.

Giovanni Ciriello, Luca Magnani, Sarah J Aitken, Leila Akkari, Sam Behjati, Douglas Hanahan, Dan A Landau, Nuria Lopez-Bigas, Darío G Lupiáñez, Jean-Christophe Marine, Ana Martin-Villalba, Gioacchino Natoli, Anna C Obenauf, Elisa Oricchio, Paola Scaffidi, Andrea Sottoriva, Alexander Swarbrick, Giovanni Tonon, Sakari Vanharanta, Johannes Zuber.

Cancer cells adapt and survive through the acquisition and selection of molecular modifications. This process defines cancer evolution. Building on a theoretical framework based on heritable genetic changes has provided insights into the mechanisms supporting cancer evolution. However, cancer hallmarks also emerge via heritable nongenetic mechanisms, including epigenetic and chromatin topological changes, and interactions between tumor cells and the tumor microenvironment. Recent findings on tumor evolutionary mechanisms draw a multifaceted picture where heterogeneous forces interact and influence each other while shaping tumor progression. A comprehensive characterization of the cancer evolutionary toolkit is required to improve personalized medicine and biomarker discovery.SIGNIFICANCE: Tumor evolution is fueled by multiple enabling mechanisms. Importantly, genetic instability, epigenetic reprogramming, and interactions with the tumor microenvironment are neither alternative nor independent evolutionary mechanisms. As demonstrated by findings highlighted in this perspective, experimental and theoretical approaches must account for multiple evolutionary mechanisms and their interactions to ultimately understand, predict, and steer tumor evolution.

DOI: https://doi.org/10.1158/2159-8290.CD-23-0530
Cancer Cell Int. 2023 Dec 06. 23(1): 310

Disclosing a metabolic signature of cisplatin resistance in MDA-MB-231 triple-negative breast cancer cells by NMR metabolomics.

Tatiana J Carneiro, Ana L M Batista Carvalho, Martin Vojtek, Inês F Carmo, Maria Paula M Marques, Carmen Diniz, Ana M Gil.

  This work compared the metabolic profile of a parental MDA-MB-231 cisplatin-sensitive triple negative breast cancer (TNBC) cell line with that of a derived cisplatin-resistant line, to characterize inherent metabolic adaptations to resistance, as a means for marker and new TNBC therapies discovery. Supported by cytotoxic, microscopic and biochemical characterization of both lines, Nuclear Magnetic Resonance (NMR) metabolomics was employed to characterize cell polar extracts for the two cell lines, as a function of time (0, 24 and 48 h), and identify statistically relevant differences both between sensitive and resistant cells and their time course behavior. Biochemical results revealed a slight increase in activation of the NF-κB pathway and a marked decrease of the ERK signaling pathway in resistant cells. This was accompanied by lower glycolytic and glutaminolytic activities, possibly linked to glutamine being required to increase stemness capacity and, hence, higher survival to cisplatin. The TCA cycle dynamics seemed to be time-dependent, with an apparent activation at 48 h preferentially supported by anaplerotic aromatic amino acids, leucine and lysine. A distinct behavior of leucine, compared to the other branched-chain-amino-acids, suggested the importance of the recognized relationship between leucine and in mTOR-mediated autophagy to increase resistance. Suggested markers of MDA-MB-231 TNBC cisplatin-resistance included higher phosphocreatine/creatine ratios, hypotaurine/taurine-mediated antioxidant protective mechanisms, a generalized marked depletion in nucleotides/nucleosides, and a distinctive pattern of choline compounds. Although the putative hypotheses generated here require biological demonstration, they pave the way to the use of metabolites as markers of cisplatin-resistance in TNBC and as guidance to develop therapies.

Keywords:  Cisplatin resistance; MDA-MB-231 cell line; Metabolic profiling; Metabolomics; Nuclear magnetic resonance; Triple negative breast cancer

DOI:  https://doi.org/10.1186/s12935-023-03124-0