bims-medica Biomed News
on Metabolism and diet in cancer
Issue of 2023–11–12
33 papers selected by
Brett Chrest, East Carolina University
  1. The role of endoplasmic reticulum stress in promoting aerobic glycolysis in cancer cells: An overview.
  2. PDP1 is a key metabolic gatekeeper and modulator of drug resistance in FLT3-ITD-positive acute myeloid leukemia.
  3. Near-Physiological Concentrations of Extracellular Pyruvate Stimulated Glucose Utilization along with Triglyceride Accumulation and Mitochondrial Activity in HepG2 Cells.
  4. Reductive stress in cancer: coming out of the shadows.
  5. Breast adipose tissue-derived extracellular vesicles from obese women alter tumor cell metabolism.
  6. The Impact of Modern Dietary Practices on Cancer Risk and Progression: A Systematic Review.
  7. SGMS1-AS1/MicroRNA-106a-5p/CPT2 Axis as a Novel Target for Regulating Lactate Metabolism in Colon Cancer.
  8. Experimental hemodialysis in diet-induced ketosis and the potential use of dialysis as an adjuvant cancer treatment.
  9. Metabolic dependencies of metastasis-initiating cells in female breast cancer.
  10. Metformin-Loaded Hyaluronic Acid-Derived Carbon Dots for Targeted Therapy against Hepatocellular Carcinoma by Glutamine Metabolic Reprogramming.
  11. Glucose deprivation promotes pseudo-hypoxia and de-differentiation in lung adenocarcinoma.
  12. SLC25A21 downregulation promotes KRAS-mutant colorectal cancer progression by increasing glutamine anaplerosis.
  13. Targeting the TCA cycle through cuproptosis confers synthetic lethality on ARID1A-deficient hepatocellular carcinoma.
  14. Current Advances on Nanomaterials Interfering with Lactate Metabolism for Tumor Therapy.
  15. The dentate gyrus differentially metabolizes glucose and alternative fuels during rest and stimulation.
  16. Shikonin exerts an anti-leukemia effect against FLT3-ITD mutated acute myeloid leukemia cells via targeting FLT3 tyrosine kinase and its downstream pathways.
  17. Venetoclax in adult acute myeloid leukemia.
  18. Regulatory mechanisms of one-carbon metabolism enzymes.
  19. 13C tracer analysis reveals the landscape of metabolic checkpoints in human CD8+ T cell differentiation and exhaustion.
  20. Hypoxia signaling and metastatic progression.
  21. Melatonin and ferroptosis: Mechanisms and therapeutic implications.
  22. Senescent tumor cells in colorectal cancer are characterized by elevated enzymatic activity of complexes 1 and 2 in oxidative phosphorylation.
  23. Fast proliferating and slowly migrating non-small cell lung cancer cells are vulnerable to decitabine and retinoic acid combinatorial treatment.
  24. Kinetic modelling of β-cell metabolism reveals control points in the insulin-regulating pyruvate cycling pathways.
  25. Establishment of a tissue-engineered colon cancer model for comparative analysis of cancer cell lines.
  26. Vitamin B5 supports MYC oncogenic metabolism and tumor progression in breast cancer.
  27. A Subset of Colon Cancer Cell Lines Displays a Cytokine Profile Linked to Angiogenesis, EMT and Invasion Which Is Modulated by the Culture Conditions In Vitro.
  28. IL-6/JAK2-dependent G6PD phosphorylation promotes nucleotide synthesis and supports tumor growth.
  29. Hypoxia promotes the growth and metastasis of ovarian cancer cells by suppressing ferroptosis via upregulating SLC2A12.
  30. Endoplasmic reticulum regulation of glucose metabolism in glioma stem cells.
  31. Targeting cholesterol metabolism in Cancer: From molecular mechanisms to therapeutic implications.
  32. Simple droplet microfluidics platform for drug screening on cancer spheroids.
  33. Dual targeting of Mcl-1 and Bcl-2 to overcome chemoresistance in cervical and colon cancer.
  1. Pathol Res Pract. 2023 Oct 24. pii: S0344-0338(23)00606-4. [Epub ahead of print]251 154905
    The role of endoplasmic reticulum stress in promoting aerobic glycolysis in cancer cells: An overview.
    Abduladheem Turki Jalil, Mohanad Ali Abdulhadi, Sami Awad Alkubaisy, Sara Hamed Thejeel, Israa M Essa, Muna S Merza, Rahman S Zabibah, Raad Al-Tamimi.
      Aerobic glycolysis, also known as the Warburg effect, is a metabolic phenomenon frequently observed in cancer cells, characterized by the preferential utilization of glucose through glycolysis, even under normal oxygen conditions. This metabolic shift provides cancer cells with a proliferative advantage and supports their survival and growth. While the Warburg effect has been extensively studied, the underlying mechanisms driving this metabolic adaptation in cancer cells remain incompletely understood. In recent years, emerging evidence has suggested a potential link between endoplasmic reticulum (ER) stress and the promotion of aerobic glycolysis in cancer cells. The ER is a vital organelle involved in protein folding, calcium homeostasis, and lipid synthesis. Various cellular stresses, such as hypoxia, nutrient deprivation, and accumulation of misfolded proteins, can lead to ER stress. In response, cells activate the unfolded protein response (UPR) to restore ER homeostasis. However, prolonged or severe ER stress can activate alternative signaling pathways that modulate cellular metabolism, including the promotion of aerobic glycolysis. This review aims to provide an overview of the current understanding regarding the influence of ER stress on aerobic glycolysis in cancer cells to shed light on the complex interplay between ER stress and metabolic alterations in cancer cells. Understanding the intricate relationship between ER stress and the promotion of aerobic glycolysis in cancer cells may provide valuable insights for developing novel therapeutic strategies targeting metabolic vulnerabilities in cancer.
    Keywords:  Aerobic Glycolysis; Endoplasmic Reticulum Stress; Metabolic Adaptation
    DOI:  https://doi.org/10.1016/j.prp.2023.154905
  2. Leukemia. 2023 Nov 07.
    PDP1 is a key metabolic gatekeeper and modulator of drug resistance in FLT3-ITD-positive acute myeloid leukemia.
    Islam Alshamleh, Nina Kurrle, Philipp Makowka, Raj Bhayadia, Rahul Kumar, Sebastian Süsser, Marcel Seibert, Damian Ludig, Sebastian Wolf, Sebastian E Koschade, Karoline Stoschek, Johanna Kreitz, Dominik C Fuhrmann, Rosa Toenges, Marco Notaro, Federico Comoglio, Jan Jacob Schuringa, Tobias Berg, Bernhard Brüne, Daniela S Krause, Jan-Henning Klusmann, Thomas Oellerich, Frank Schnütgen, Harald Schwalbe, Hubert Serve.
      High metabolic flexibility is pivotal for the persistence and therapy resistance of acute myeloid leukemia (AML). In 20-30% of AML patients, activating mutations of FLT3, specifically FLT3-ITD, are key therapeutic targets. Here, we investigated the influence of FLT3-ITD on AML metabolism. Nuclear Magnetic Resonance (NMR) profiling showed enhanced reshuffling of pyruvate towards the tricarboxylic acid (TCA) cycle, suggesting an increased activity of the pyruvate dehydrogenase complex (PDC). Consistently, FLT3-ITD-positive cells expressed high levels of PDP1, an activator of the PDC. Combining endogenous tagging of PDP1 with genome-wide CRISPR screens revealed that FLT3-ITD induces PDP1 expression through the RAS signaling axis. PDP1 knockdown resulted in reduced cellular respiration thereby impairing the proliferation of only FLT3-ITD cells. These cells continued to depend on PDP1, even in hypoxic conditions, and unlike FLT3-ITD-negative cells, they exhibited a rapid, PDP1-dependent revival of their respiratory capacity during reoxygenation. Moreover, we show that PDP1 modifies the response to FLT3 inhibition. Upon incubation with the FLT3 tyrosine kinase inhibitor quizartinib (AC220), PDP1 persisted or was upregulated, resulting in a further shift of glucose/pyruvate metabolism towards the TCA cycle. Overexpression of PDP1 enhanced, while PDP1 depletion diminished AC220 resistance in cell lines and peripheral blasts from an AC220-resistant AML patient in vivo. In conclusion, FLT3-ITD assures the expression of PDP1, a pivotal metabolic regulator that enhances oxidative glucose metabolism and drug resistance. Hence, PDP1 emerges as a potentially targetable vulnerability in the management of AML.
    DOI:  https://doi.org/10.1038/s41375-023-02041-5
  3. J Nutr Sci Vitaminol (Tokyo). 2023 ;69(5): 314-325
    Near-Physiological Concentrations of Extracellular Pyruvate Stimulated Glucose Utilization along with Triglyceride Accumulation and Mitochondrial Activity in HepG2 Cells.
    Misaki Kurawaka, Naho Sasaki, Yuko Yamazaki, Fumio Shimura.
      Pyruvate, a key intermediate in energy and nutrient metabolism, probably plays important roles in these regulations. In previous reports using cell lines, extracellular pyruvate of supraphysiological concentrations inhibited the glucose uptake by myotubes while being stimulated by adipocytes. As the effect of pyruvate on the glucose utilization is unclear in cultured hepatocytes. We have investigated the effects of extracellular pyruvate on the glucose utilization and the subsequent metabolic changes using the cell line HepG2. In a 24 h culture, pyruvate enhanced the glucose consumption more potently than 1 μM insulin, and this enhancement was detectable at a near-physiological concentrations of ≤1 mM. For metabolic changes following glucose consumption, the conversion ratio of glucose and pyruvate to extracellular lactate was approximately 1.0 without extracellular pyruvate. The addition of pyruvate decreased the conversion ratio to approximately 0.7, indicating that the glycolytic reaction switched from being an anaerobic to a partially aerobic feature. Consistent with this finding, pyruvate increased the accumulation of intracellular triglycerides which are produced through substrate supply from the mitochondria. Furthermore, pyruvate stimulated mitochondria activity as evidenced by increases in ATP content, mitochondrial DNA copy number, enhanced mitochondria-specific functional imaging and oxygen consumption. Interestingly, 1 mM pyruvate increased oxygen consumption immediately after addition. In this study, we found that near-physiological concentrations of extracellular pyruvate exerted various changes in metabolic events, including glucose influx, lactate conversion rations, TG accumulation, and mitochondrial activity in HepG2 cells.
    Keywords:  HepG2; glucose metabolism; hepatocyte; mitochondria; pyruvate
    DOI:  https://doi.org/10.3177/jnsv.69.314
  4. Trends Cancer. 2023 Nov 02. pii: S2405-8033(23)00213-3. [Epub ahead of print]
    Reductive stress in cancer: coming out of the shadows.
    Maolin Ge, Thales Papagiannakopoulos, Liron Bar-Peled.
      Redox imbalance is defined by disruption in oxidative and reductive pathways and has a central role in cancer initiation, development, and treatment. Although redox imbalance has traditionally been characterized by high levels of oxidative stress, emerging evidence suggests that an overly reductive environment is just as detrimental to cancer proliferation. Reductive stress is defined by heightened levels of antioxidants, including glutathione and elevated NADH, compared with oxidized NAD, which disrupts central biochemical pathways required for proliferation. With the advent of new technologies that measure and manipulate reductive stress, the sensors and drivers of this overlooked metabolic stress are beginning to be revealed. In certain genetically defined cancers, targeting reductive stress pathways may be an effective strategy. Redox-based pathways are gaining recognition as essential 'regulatory hubs,' and a broader understanding of reductive stress signaling promises not only to reveal new insights into metabolic homeostasis but also potentially to transform therapeutic options in cancer.
    Keywords:  KEAP1/NRF2; cancer metabolism; redox homeostasis; reductive stress
    DOI:  https://doi.org/10.1016/j.trecan.2023.10.002
  5. EMBO Rep. 2023 Nov 06. e57339
    Breast adipose tissue-derived extracellular vesicles from obese women alter tumor cell metabolism.
    Shuchen Liu, Alberto Benito-Martin, Fanny A Pelissier Vatter, Sarah Z Hanif, Catherine Liu, Priya Bhardwaj, Praveen Sethupathy, Alaa R Farghli, Phoebe Piloco, Paul Paik, Malik Mushannen, Xue Dong, David M Otterburn, Leslie Cohen, Rohan Bareja, Jan Krumsiek, Leona Cohen-Gould, Samuel Calto, Jason A Spector, Olivier Elemento, David C Lyden, Kristy A Brown.
      Breast adipose tissue is an important contributor to the obesity-breast cancer link. Extracellular vesicles (EVs) are nanosized particles containing selective cargo, such as miRNAs, that act locally or circulate to distant sites to modulate target cell functions. Here, we find that long-term education of breast cancer cells with EVs obtained from breast adipose tissue of women who are overweight or obese (O-EVs) results in increased proliferation. RNA-seq analysis of O-EV-educated cells demonstrates increased expression of genes involved in oxidative phosphorylation, such as ATP synthase and NADH: ubiquinone oxidoreductase. O-EVs increase respiratory complex protein expression, mitochondrial density, and mitochondrial respiration in tumor cells. The mitochondrial complex I inhibitor metformin reverses O-EV-induced cell proliferation. Several miRNAs-miR-155-5p, miR-10a-3p, and miR-30a-3p-which promote mitochondrial respiration and proliferation, are enriched in O-EVs relative to EVs from lean women. O-EV-induced proliferation and mitochondrial activity are associated with stimulation of the Akt/mTOR/P70S6K pathway, and are reversed upon silencing of P70S6K. This study reveals a new facet of the obesity-breast cancer link with human breast adipose tissue-derived EVs causing metabolic reprogramming of breast cancer cells.
    Keywords:  breast cancer; extracellular vesicles; mitochondrial respiration; obesity; proliferation
    DOI:  https://doi.org/10.15252/embr.202357339
  6. Cureus. 2023 Oct;15(10): e46639
    The Impact of Modern Dietary Practices on Cancer Risk and Progression: A Systematic Review.
    Stephanie Nagy, Stephanie N Petrosky, Michelle Demory Beckler, Marc M Kesselman.
      Cancer is a leading cause of mortality around the world, despite continued advancements in the management of cancer. Recent research efforts have shifted to evaluating the role that modifiable risk factors play in cancer risk and development, as diet and nutrition have been found to play a significant role in the onset and progression of cancer. As a result, there has been an increasing focus on the impact of dietary modifications on preventing the onset, progression, and reoccurrence of cancer. In this systematic review, data were collected on three common diets, the Mediterranean diet (MD), ketogenic diet (KD), and plant-based diet, to gain insight into the application of these three dietary modification approaches for risk prevention and limitation of cancer burden. Initially, 4,397 articles were identified from three databases (Ovid, Web of Science, and CINHAL). After removing studies based on the exclusion criteria, only 23 studies were eligible to be included in the systematic review of which 15 evaluated the MD, four assessed the ketogenic diet, and four evaluated the plant-based diet. Each article was considered for its methods, procedures, and findings. The findings indicate that dietary interventions may effectively reduce the odds of cancer development and the advancement of diagnosed cancers. With the introduction of the MD, KD, and plant-based diets, significant improvements in lowering cancer development, recurrence-free status, and limiting tumor growth were noted across numerous cancer types. Currently, the MD has been extensively studied in the literature, and amongst the widest variety of cancer types. Additional information and evaluation are required on the ketogenic and plant-based diets to fully understand their impact on the cancer burden across a wider subset of cancers. Clinicians should evaluate and recommend nutritional adaptations to their patients to limit the development of specific cancers and as an adjunctive therapy to traditional pharmacological treatment options for patients with diagnosed cancers.
    Keywords:  cancer; diet; ketogenic diet; mediterranean diet; nutrition; plant-based diet
    DOI:  https://doi.org/10.7759/cureus.46639
  7. Technol Cancer Res Treat. 2023 Jan-Dec;22:22 15330338231212071
    SGMS1-AS1/MicroRNA-106a-5p/CPT2 Axis as a Novel Target for Regulating Lactate Metabolism in Colon Cancer.
    Yan Ruochen, Ji Wenbin, Gao Chao, Yuan Yuhua, Qi Feng.
       PURPOSE: The malignant transformation of cells can lead to aerobic glycolysis, an important form of metabolic reprogramming in colon cancer cells, which can cause the accumulation of lactate and accelerate the proliferation of tumor cells also enhance their chemotherapy drug resistance. The aim of this study was to investigate the possible molecular mechanisms responsible for the increased lactate expression in colon cancer.
    METHODS: Several bioinformatics methods, including differential analysis, gene ontology enrichment, univariate and multivariate Cox regression analysis were used to find the lactic acid-related gene carnitine palmitoyltransferase 2. We analyzed the relationship between carnitine palmitoyltransferase 2 and clinical features as well as immune microenvironment. To further explore the mechanism of carnitine palmitoyltransferase 2 in colon cancer, we performed methylation analysis and constructed a competitive endogenous RNA network, which was validated in cell lines and clinical specimens.
    RESULTS: We used bioinformatics to select the lactic acid-related gene carnitine palmitoyltransferase 2 and found low expression of carnitine palmitoyltransferase 2 was associated with poor prognosis in colon cancer. An inhibitory tumor microenvironment was created when carnitine palmitoyltransferase 2 expression was reduced, with decreased CD4 T cells, CD8 T cells, dendritic cells, and B cells but increased cancer-associated fibroblasts. Methylation analysis showed that the abnormal decrease in carnitine palmitoyltransferase 2 might be caused by hypermethylation. We constructed a network of SGMS1-AS1/microRNA-106a-5p/carnitine palmitoyltransferase 2 and verified their expression in cell lines and clinical specimens.
    CONCLUSION: Our work revealed the possible mechanism of lactate accumulation in colon cancer and explored a new potential treatment for colon cancer by cutting off aerobic glycolysis in tumor cells.
    Keywords:  ceRNA; colon cancer; glycolysis; lactate; metabolic reprogramming
    DOI:  https://doi.org/10.1177/15330338231212071
  8. Sci Rep. 2023 Nov 09. 13(1): 19476
    Experimental hemodialysis in diet-induced ketosis and the potential use of dialysis as an adjuvant cancer treatment.
    Carl M Öberg, Jan Sternby, Anders Nilsson, Markus Storr, Ralf Flieg, Kai Harenski, Viktoria Roos, Linda Källquist, Sture Hobro.
      Numerous in vivo studies on the ketogenic diet, a diet that can induce metabolic conditions resembling those following extended starvation, demonstrate strong outcomes on cancer survival, particularly when combined with chemo-, radio- or immunological treatments. However, the therapeutic application of ketogenic diets requires strict dietary adherence from well-informed and motivated patients, and it has recently been proposed that hemodialysis might be utilized to boost ketosis and further destabilize the environment for cancer cells. Yet, plasma ketones may be lost in the dialysate-lowering blood ketone levels. Here we performed a single 180-min experimental hemodialysis (HD) session in six anesthetized Sprague-Dawley rats given ketogenic diet for five days. Median blood ketone levels pre-dialysis were 3.5 mmol/L (IQR 2.2 to 5.6) and 3.8 mmol/L (IQR 2.2 to 5.1) after 180 min HD, p = 0.54 (95% CI - 0.6 to 1.2). Plasma glucose levels were reduced by 36% (- 4.5 mmol/L), p < 0.05 (95% CI - 6.7 to - 2.5). Standard base excess was increased from - 3.5 mmol/L (IQR - 4 to - 2) to 0.5 mmol/L (IQR - 1 to 3), p < 0.01 (95% CI 2.0 to 5.0). A theoretical model was applied confirming that intra-dialytic glucose levels decrease, and ketone levels slightly increase since hepatic ketone production far exceeds dialytic removal. Our experimental data and in-silico modeling indicate that elevated blood ketone levels during ketosis are maintained during hemodialysis despite dialytic removal.
    DOI:  https://doi.org/10.1038/s41598-023-46715-7
  9. Nat Commun. 2023 Nov 04. 14(1): 7076
    Metabolic dependencies of metastasis-initiating cells in female breast cancer.
    C Megan Young, Laurent Beziaud, Pierre Dessen, Angela Madurga Alonso, Albert Santamaria-Martínez, Joerg Huelsken.
      Understanding the mechanisms that enable cancer cells to metastasize is essential in preventing cancer progression. Here we examine the metabolic adaptations of metastasis-initiating cells (MICs) in female breast cancer and how those shape their metastatic phenotype. We find that endogenous MICs depend on the oxidative tricarboxylic acid cycle and fatty acid usage. Sorting tumor cells based upon solely mitochondrial membrane potential or lipid storage is sufficient at identifying MICs. We further identify that mitochondrially-generated citrate is exported to the cytoplasm to yield acetyl-CoA, and this is crucial to maintaining heightened levels of H3K27ac in MICs. Blocking acetyl-CoA generating pathways or H3K27ac-specific epigenetic writers and readers reduces expression of epithelial-to-mesenchymal related genes, MIC frequency, and metastatic potential. Exogenous supplementation of a short chain carboxylic acid, acetate, increases MIC frequency and metastasis. In patient cohorts, we observe that higher expression of oxidative phosphorylation related genes is associated with reduced distant relapse-free survival. These data demonstrate that MICs specifically and precisely alter their metabolism to efficiently colonize distant organs.
    DOI:  https://doi.org/10.1038/s41467-023-42748-8
  10. Mol Pharm. 2023 Nov 07.
    Metformin-Loaded Hyaluronic Acid-Derived Carbon Dots for Targeted Therapy against Hepatocellular Carcinoma by Glutamine Metabolic Reprogramming.
    Aparajita Ghosh, Anup Kumar Ghosh, Afreen Zaman, Prasanta Kumar Das.
      Metabolic reprogramming is a significant hallmark of cancer that promotes chemoresistance by allowing tumor tissues to adapt to changes in the tumor microenvironment caused by anticancer therapies. Hepatocellular carcinoma (HCC), one of the most common types of primary tumors, is associated with recurrent metabolic reprogramming that maximizes cancer cell growth and proliferation. Herein, we developed metformin (MET)-loaded hyaluronic acid (HA)-derived carbon dots (HA-CD-MET) by a simple and green method with no involvement of any additives. HA-CD-MET was utilized for specifically binding the CD44 receptor overexpressed in HCC and induced glutamine metabolic rewiring to inhibit HCC cell proliferation. Exposure to HA-CD-MET resulted in ∼6.5-fold better anticancer efficacy against CD44+ Hep3B cells in comparison to CD44-, HepG2, and noncancerous HEK293 cells at a very low dose of 80 μg/mL. Moreover, treatment of three-dimensional (3D) tumor spheroid model of HCC (Hep3B) with HA-CD-MET resulted in ∼4.9-fold reduction in tumor size. This improved anticancer efficacy of HA-CD-MET was attributed to the inhibition of glutaminase-1 (GLS-1), a mitochondrial enzyme that hydrolyzes glutamine into glutamate as confirmed from immunofluorescence and immunoblotting experiments. Furthermore, treatment with HA-CD-MET resulted in downregulation of glucose transporter-1 (GLUT-1) in Hep3B cells. Consequently, cancer cells were starved from essential nutrients, glutamine, and glucose, leading to the enhancement in intracellular ROS generation. This increase in intracellular ROS accumulation activated AMP-activated protein kinase (AMPK) and inhibited AKT phosphorylation, leading to cancer cell apoptosis. Thus, this study offers the targeting of metabolic reprogramming by HA-CD-MET that opens up a promising strategy for therapeutic intervention in hepatocarcinoma.
    Keywords:  CD44; carbon dot; glutamine; hyaluronic acid; metabolic reprogramming; metformin
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.3c00772
  11. Cancer Res. 2023 11 07.
    Glucose deprivation promotes pseudo-hypoxia and de-differentiation in lung adenocarcinoma.
    Pasquale Saggese, Aparamita Pandey, Martín Alcaraz, Eileen Fung, Abbie Hall, Jane Yanagawa, Erika F Rodriguez, Tristan R Grogan, Giorgio Giurato, Giovanni Nassa, Annamaria Salvati, Orian S Shirihai, Alessandro Weisz, Steven M Dubinett, Claudio Scafoglio.
      Increased utilization of glucose is a hallmark of cancer. Sodium-glucose transporter 2 (SGLT2) is a critical player in glucose uptake in early-stage and well-differentiated lung adenocarcinoma (LUAD). SGLT2 inhibitors, which are FDA-approved for diabetes, heart failure, and kidney disease, have been shown to significantly delay LUAD development and prolong survival in murine models and in retrospective studies in diabetic patients, suggesting that they may be re-purposed for lung cancer. Despite the anti-tumor effects of SGLT2 inhibition, tumors eventually escape treatment. Here, we studied the mechanisms of resistance to glucose metabolism-targeting treatments. Glucose restriction in LUAD and other tumors induced cancer cell de-differentiation, leading to a more aggressive phenotype. Glucose deprivation caused a reduction in alpha-ketoglutarate (αKG), leading to attenuated activity of αKG-dependent histone demethylases and histone hypermethylation. The de-differentiated phenotype depended on unbalanced EZH2 activity that suppressed prolyl-hydroxylase PHD3 and increased expression of hypoxia inducible factor 1α (HIF1α), triggering epithelial-to-mesenchymal transition. Finally, a HIF1α-dependent transcriptional signature of genes up-regulated by low glucose correlated with prognosis in human LUAD. Overall, this study furthers current knowledge of the relationship between glucose metabolism and cell differentiation in cancer, characterizing the epigenetic adaptation of cancer cells to glucose deprivation and identifying targets to prevent the development of resistance to therapies targeting glucose metabolism.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-1148
  12. JCI Insight. 2023 Nov 08. pii: e167874. [Epub ahead of print]8(21):
    SLC25A21 downregulation promotes KRAS-mutant colorectal cancer progression by increasing glutamine anaplerosis.
    Sha-Sha Hu, Yue Han, Tian-Yuan Tan, Hui Chen, Jia-Wen Gao, Lan Wang, Min-Hui Yang, Li Zhao, Yi-Qing Wang, Yan-Qing Ding, Shuang Wang.
      Emerging evidence shows that KRAS-mutant colorectal cancer (CRC) depends on glutamine (Gln) for survival and progression, indicating that targeting Gln metabolism may be a promising therapeutic strategy for KRAS-mutant CRC. However, the precise mechanism by which Gln metabolism reprogramming promotes and coordinates KRAS-mutant CRC progression remains to be fully investigated. Here, we discovered that solute carrier 25 member 21 (SLC25A21) expression was downregulated in KRAS-mutant CRC, and that SLC25A21 downregulation was correlated with poor survival of KRAS-mutant CRC patients. SLC25A21 depletion selectively accelerated the growth, invasion, migration, and metastasis of KRAS-mutant CRC cells in vitro and in vivo, and inhibited Gln-derived α-ketoglutarate (α-KG) efflux from mitochondria, thereby potentiating Gln replenishment, accompanied by increased GTP availability for persistent KRAS activation in KRAS-mutant CRC. The restoration of SLC25A21 expression impaired the KRAS-mutation-mediated resistance to cetuximab in KRAS-mutant CRC. Moreover, the arrested α-KG efflux that occurred in response to SLC25A21 depletion inhibited the activity of α-KG-dependent DNA demethylases, resulting in a further decrease in SLC25A21 expression. Our studies demonstrate that SLC25A21 plays a significant role as a tumor suppressor in KRAS-mutant CRC by antagonizing Gln-dependent anaplerosis to limit GTP availability for KRAS activation, which suggests potential alternative therapeutic strategies for KRAS-mutant CRC.
    Keywords:  Amino acid metabolism; Colorectal cancer; Drug therapy; Gastroenterology; Metabolism
    DOI:  https://doi.org/10.1172/jci.insight.167874
  13. Cell Rep Med. 2023 Oct 31. pii: S2666-3791(23)00441-X. [Epub ahead of print] 101264
    Targeting the TCA cycle through cuproptosis confers synthetic lethality on ARID1A-deficient hepatocellular carcinoma.
    Tao Xing, Li Li, Yiran Chen, Gaoda Ju, Guilan Li, Xiaoyun Zhu, Yubo Ren, Jing Zhao, Zhilei Cheng, Yan Li, Da Xu, Jun Liang.
      ARID1A is among the most commonly mutated tumor suppressor genes in hepatocellular carcinoma (HCC). In this study, we conduct a CRISPR-Cas9 synthetic lethality screen using ARID1A-deficient HCC cells to identify approaches to treat HCC patients harboring ARID1A deficiency. This strategy reveals that the survival of these ARID1A-deficient HCC cells is highly dependent on genes related to the tricarboxylic acid (TCA) cycle. Mechanistically, ARID1A loss represses expression of key glycolysis-related gene PKM, shifting cellular glucose metabolism from aerobic glycolysis to dependence on the TCA cycle and oxidative phosphorylation. Cuproptosis is a recently defined form of copper-induced cell death reported to directly target the TCA cycle. Here, we find that ARID1A-deficient HCC cells and xenograft tumors are highly sensitive to copper treatment. Together, these results offer evidence of the synthetic lethality between ARID1A deficiency and mitochondrial respiration impairment, suggesting that copper treatment constitutes a promising therapeutic strategy for selectively targeting ARID1A-deficient HCC.
    DOI:  https://doi.org/10.1016/j.xcrm.2023.101264
  14. Adv Sci (Weinh). 2023 Nov 08. e2305662
    Current Advances on Nanomaterials Interfering with Lactate Metabolism for Tumor Therapy.
    Qian Cheng, Xiao-Lei Shi, Qi-Lin Li, Lin Wang, Zheng Wang.
      Increasing numbers of studies have shown that tumor cells prefer fermentative glycolysis over oxidative phosphorylation to provide a vast amount of energy for fast proliferation even under oxygen-sufficient conditions. This metabolic alteration not only favors tumor cell progression and metastasis but also increases lactate accumulation in solid tumors. In addition to serving as a byproduct of glycolytic tumor cells, lactate also plays a central role in the construction of acidic and immunosuppressive tumor microenvironment, resulting in therapeutic tolerance. Recently, targeted drug delivery and inherent therapeutic properties of nanomaterials have attracted great attention, and research on modulating lactate metabolism based on nanomaterials to enhance antitumor therapy has exploded. In this review, the advanced tumor therapy strategies based on nanomaterials that interfere with lactate metabolism are discussed, including inhibiting lactate anabolism, promoting lactate catabolism, and disrupting the "lactate shuttle". Furthermore, recent advances in combining lactate metabolism modulation with other therapies, including chemotherapy, immunotherapy, photothermal therapy, and reactive oxygen species-related therapies, etc., which have achieved cooperatively enhanced therapeutic outcomes, are summarized. Finally, foreseeable challenges and prospective developments are also reviewed for the future development of this field.
    Keywords:  glycolysis; lactate metabolism; nanoparticles; tumor therapy
    DOI:  https://doi.org/10.1002/advs.202305662
  15. J Neurochem. 2023 Nov 06.
    The dentate gyrus differentially metabolizes glucose and alternative fuels during rest and stimulation.
    Elisa M York, Anne Miller, Sylwia A Stopka, Juan Ramón Martínez-François, Md Amin Hossain, Gerard Baquer, Michael S Regan, Nathalie Y R Agar, Gary Yellen.
      The metabolic demands of neuronal activity are both temporally and spatially dynamic, and neurons are particularly sensitive to disruptions in fuel and oxygen supply. Glucose is considered an obligate fuel for supporting brain metabolism. Although alternative fuels are often available, the extent of their contribution to central carbon metabolism remains debated. Differential fuel metabolism likely depends on cell type, location, and activity state, complicating its study. While biosensors provide excellent spatial and temporal information, they are limited to observations of only a few metabolites. On the other hand, mass spectrometry is rich in chemical information, but traditionally relies on cell culture or homogenized tissue samples. Here, we use mass spectrometry imaging (MALDI-MSI) to focus on the fuel metabolism of the dentate granule cell (DGC) layer in murine hippocampal slices. Using stable isotopes, we explore labeling dynamics at baseline, as well as in response to brief stimulation or fuel competition. We find that at rest, glucose is the predominant fuel metabolized through glycolysis, with little to no measurable contribution from glycerol or fructose. However, lactate/pyruvate, β-hydroxybutyrate (βHB), octanoate, and glutamine can contribute to TCA metabolism to varying degrees. In response to brief depolarization with 50 mM KCl, glucose metabolism was preferentially increased relative to the metabolism of alternative fuels. With an increased supply of alternative fuels, both lactate/pyruvate and βHB can outcompete glucose for TCA cycle entry. While lactate/pyruvate modestly reduced glucose contribution to glycolysis, βHB caused little change in glycolysis. This approach achieves broad metabolite coverage from a spatially defined region of physiological tissue, in which metabolic states are rapidly preserved following experimental manipulation. Using this powerful methodology, we investigated metabolism within the dentate gyrus not only at rest, but also in response to the energetic demand of activation, and in states of fuel competition.
    Keywords:  brain metabolism; glucose metabolism; ketone body metabolism; lactate metabolism; mass spectrometry imaging; stable isotope tracing
    DOI:  https://doi.org/10.1111/jnc.16004
  16. Acta Haematol. 2023 Nov 03.
    Shikonin exerts an anti-leukemia effect against FLT3-ITD mutated acute myeloid leukemia cells via targeting FLT3 tyrosine kinase and its downstream pathways.
    Mu-Nan Zhao, Long Su, Fei Song, Zhi-Feng Wei, Tian-Xue Qin, Yun-Wei Zhang, Wei Li, Su-Jun Gao.
       INTRODUCTION: Acute myeloid leukemia (AML) with internal tandem duplication (ITD) mutations in Fms-like tyrosine kinase 3 (FLT3) has an unfavorable prognosis. Recently, using newly emerging inhibitors of FLT3 has led to improved outcomes of patients with FLT3-ITD mutations. However, drug resistance and relapse continue to be significant challenges in the treatment of patients with FLT3-ITD mutations. This study aimed to evaluate the anti-leukemic effects of shikonin (SHK) and its mechanisms of action against AML cells with FLT3-ITD mutations in vitro and in vivo.
    METHODS: The CCK-8 assay was used to analyze cell viability, and flow cytometry was used to detect cell apoptosis and differentiation. Western blotting and real-time polymerase chain reaction (RT-PCR) were used to examine the expression of certain proteins and genes. Leukemia mouse model was created to evaluate the anti-leukemia effect of SHK against FLT3-ITD mutated leukemia in vivo.
    RESULTS: After screening a series of leukemia cell lines, those with FLT3-ITD mutations were found to be more sensitive to SHK in terms of proliferation inhibition and apoptosis induction than those without FLT3-ITD mutations. SHK suppresses the expression and phosphorylation of FLT3 receptors and their downstream molecules. Inhibition of the NF-κB/miR-155 pathway is an important mechanism through which SHK kills FLT3-AML cells. Moreover, a low concentration of SHK promotes the differentiation of AML cells with FLT3-ITD mutations. Finally, SHK could significantly inhibit the growth of MV4-11 cells in leukemia bearing mice.
    CONCLUSION: The findings of this study indicate that SHK is a promising drug for the treatment of FLT3-ITD mutated AML.
    DOI:  https://doi.org/10.1159/000534101
  17. Biomed Pharmacother. 2023 Nov 03. pii: S0753-3322(23)01618-9. [Epub ahead of print]168 115820
    Venetoclax in adult acute myeloid leukemia.
    Mengci Hu, Wenzhe Li, Youshan Zhang, Caixia Liang, Jie Tan, Ya Wang.
      Venetoclax is a potent inhibitor that specifically targets B-cell lymphoma-2 (BCL-2), which has been demonstrated to be effective in preclinical studies utilizing acute myeloid leukemia (AML) cell lines and xenograft models. Significant antileukemic activity was also observed in clinical trials, both as a monotherapy and in combination with other drugs. This novel therapeutic approach has revolutionized the treatment prospects for AML patients with unfavorable prognoses and those who are unable to tolerate intensive chemotherapy. Nevertheless, further investigations are required to establish the optimal dosing, sequencing, and combinational strategies of venetoclax for AML treatments. Additionally, identifying biomarkers is crucial for predicting response and resistance to this targeted intervention. In this review, we provide an overview of venetoclax-based therapy for AML and explore potential avenues for future research.
    Keywords:  Acute myeloid leukemia; Combinatorial regimens; Venetoclax
    DOI:  https://doi.org/10.1016/j.biopha.2023.115820
  18. J Biol Chem. 2023 Nov 08. pii: S0021-9258(23)02485-7. [Epub ahead of print] 105457
    Regulatory mechanisms of one-carbon metabolism enzymes.
    Boryana Petrova, Adam G Maynard, Peng Wang, Naama Kanarek.
      One-carbon metabolism is a central metabolic pathway critical for the biosynthesis of several amino acids, methyl group donors, and nucleotides. The pathway mostly relies on the transfer of a carbon unit from the amino acid serine, through the cofactor folate (in its several forms), and to the ultimate carbon acceptors that include nucleotides and methyl groups used for methylation of proteins, RNA, and DNA. Nucleotides are required for DNA replication, DNA repair, gene expression, and protein translation, through ribosomal RNA. Therefore, the one-carbon metabolism pathway is essential for cell growth and function in all cells, but is specifically important for rapidly proliferating cells. The regulation of one-carbon metabolism is a critical aspect of the normal and pathological function of the pathway, such as in cancer, where hijacking these regulatory mechanisms feeds an increased need for nucleotides. One-carbon metabolism is regulated at several levels: via gene expression, posttranslational modification, sub-cellular compartmentalization, allosteric inhibition, and feedback regulation. In this review we aim to inform the readers of relevant one-carbon metabolism regulation mechanisms, and to bring forward the need to further study this aspect of one-carbon metabolism. The review aims to integrate two major aspects of cancer metabolism - signaling downstream of nutrient sensing, and one-carbon metabolism, because while each of these is critical for the proliferation of cancerous cells, their integration is critical for comprehensive understating of cellular metabolism in transformed cells and can lead to clinically-relevant insights.
    Keywords:  allosteric inhibition; cancer metabolism; metabolic adaptation; metabolic compartmentalization; post-translational modifications; transcriptional regulation
    DOI:  https://doi.org/10.1016/j.jbc.2023.105457
  19. Front Immunol. 2023 ;14 1267816
    13C tracer analysis reveals the landscape of metabolic checkpoints in human CD8+ T cell differentiation and exhaustion.
    Alexander Kirchmair, Niloofar Nemati, Giorgia Lamberti, Marcel Trefny, Anne Krogsdam, Anita Siller, Paul Hörtnagl, Petra Schumacher, Sieghart Sopper, Adolf Sandbichler, Alfred Zippelius, Bart Ghesquière, Zlatko Trajanoski.
       Introduction: Naïve T cells remain in an actively maintained state of quiescence until activation by antigenic signals, upon which they start to proliferate and generate effector cells to initiate a functional immune response. Metabolic reprogramming is essential to meet the biosynthetic demands of the differentiation process, and failure to do so can promote the development of hypofunctional exhausted T cells.
    Methods: Here we used 13C metabolomics and transcriptomics to study the metabolism of CD8+ T cells in their complete course of differentiation from naïve over stem-like memory to effector cells and in exhaustion-inducing conditions.
    Results: The quiescence of naïve T cells was evident in a profound suppression of glucose oxidation and a decreased expression of ENO1, downstream of which no glycolytic flux was detectable. Moreover, TCA cycle activity was low in naïve T cells and associated with a downregulation of SDH subunits. Upon stimulation and exit from quiescence, the initiation of cell growth and proliferation was accompanied by differential expression of metabolic enzymes and metabolic reprogramming towards aerobic glycolysis with high rates of nutrient uptake, respiration and lactate production. High flux in anabolic pathways imposed a strain on NADH homeostasis, which coincided with engagement of the proline cycle for mitochondrial redox shuttling. With acquisition of effector functions, cells increasingly relied on glycolysis as opposed to oxidative phosphorylation, which was, however, not linked to changes in mitochondrial abundance. In exhaustion, decreased effector function concurred with a reduction in mitochondrial metabolism, glycolysis and amino acid import, and an upregulation of quiescence-associated genes, TXNIP and KLF2, and the T cell suppressive metabolites succinate and itaconate.
    Discussion: Overall, these results identify multiple metabolic features that regulate quiescence, proliferation and effector function, but also exhaustion of CD8+ T cells during differentiation. Thus, targeting these metabolic checkpoints may be a promising therapeutic strategy for both prevention of exhaustion and promotion of stemness of anti-tumor T cells.
    Keywords:  13C tracer analysis; RNA sequencing; differentiation; exhaustion; immunometabolism; stem cell memory cells
    DOI:  https://doi.org/10.3389/fimmu.2023.1267816
  20. Semin Cancer Biol. 2023 Nov 03. pii: S1044-579X(23)00134-7. [Epub ahead of print]
    Hypoxia signaling and metastatic progression.
    Luana Schito, Sergio Rey-Keim.
      Disruption of oxygen homeostasis, resulting from an imbalance between O2 supply and demand during malignant proliferation, leads to the development of hypoxic tumor microenvironments that promote the acquisition of aggressive cancer cell phenotypes linked to metastasis and patient mortality. In this review, the mechanistic links between tumor hypoxia and metastatic progression are presented. Current status and perspectives of targeting hypoxia signaling pathways as a strategy to halt cancer cell metastatic activities are emphasized.
    Keywords:  Cancer; HIFs; UPR; hypoxia; invasion; metastasis; migration
    DOI:  https://doi.org/10.1016/j.semcancer.2023.11.001
  21. Biochem Pharmacol. 2023 Nov 04. pii: S0006-2952(23)00502-6. [Epub ahead of print] 115909
    Melatonin and ferroptosis: Mechanisms and therapeutic implications.
    Dongni Zhang, Xiaotong Jia, Duomao Lin, Jun Ma.
      Ferroptosis, a regulated form of cell death, is characterized by iron-dependent lipid peroxidation leading to oxidative damage to cell membranes. Cell sensitivity to ferroptosis is influenced by factors such as iron overload, lipid metabolism, and the regulation of the antioxidant system. Melatonin, with its demonstrated capacity to chelate iron, modulate iron metabolism proteins, regulate lipid peroxidation, and regulate antioxidant systems, has promise as a potential therapeutic agent in mediating ferroptosis. The availability of approved drugs targeting ferroptosis is limited; therefore, melatonin is a candidate for broad application due to its safety and efficacy in attenuating ferroptosis in noncancerous diseases. Melatonin has been demonstrated to attenuate ferroptosis in cellular and animal models of noncancerous diseases, showcasing effectiveness in organs such as the heart, brain, lung, liver, kidney, and bone. This review outlines the molecular mechanisms of ferroptosis, investigates melatonin's potential effects on ferroptosis, and discusses melatonin's therapeutic potential as a promising intervention against diseases associated with ferroptosis. Through this discourse, we aim to lay a strong foundation for developing melatonin as a therapeutic strategy to modulate ferroptosis in a variety of disease contexts.
    Keywords:  Antioxidant; Ferroptosis; Iron metabolism; Lipid peroxidation; Melatonin
    DOI:  https://doi.org/10.1016/j.bcp.2023.115909
  22. J Pathol Transl Med. 2023 Nov 07.
    Senescent tumor cells in colorectal cancer are characterized by elevated enzymatic activity of complexes 1 and 2 in oxidative phosphorylation.
    Jun Sang Shin, Tae-Gyu Kim, Young Hwa Kim, So Yeong Eom, So Hyun Park, Dong Hyun Lee, Tae Jun Park, Soon Sang Park, Jang-Hee Kim.
       Background: Cellular senescence is defined as an irreversible cell cycle arrest caused by various internal and external insults. While the metabolic dysfunction of senescent cells in normal tissue is relatively well-established, there is a lack of information regarding the metabolic features of senescent tumor cells.
    Methods: Publicly available single-cell RNA-sequencing data from the GSE166555 and GSE178341 datasets were utilized to investigate the metabolic features of senescent tumor cells. To validate the single-cell RNA-sequencing data, we performed senescence-associated β-galactosidase (SA-β-Gal) staining to identify senescent tumor cells in fresh frozen colorectal cancer tissue. We also evaluated nicotinamide adenine dinucleotide dehydrogenase-tetrazolium reductase (NADH-TR) and succinate dehydrogenase (SDH) activity using enzyme histochemical methods and compared the staining with SA-β-Gal staining. MTT assay was performed to reveal the complex 1 activity of the respiratory chain in in-vitro senescence model.
    Results: Single-cell RNA-sequencing data revealed an upregulation in the activity of complexes 1 and 2 in oxidative phosphorylation, despite overall mitochondrial dysfunction in senescent tumor cells. Both SA-β-Gal and enzyme histochemical staining using fresh frozen colorectal cancer tissues indicated a high correlation between SA-β-Gal positivity and NADH-TR/SDH staining positivity. MTT assay showed that senescent colorectal cancer cells exhibit higher absorbance in 600 nm wavelength.
    Conclusions: Senescent tumor cells exhibit distinct metabolic features, characterized by upregulation of complexes 1 and 2 in the oxidative phosphorylation pathway. NADH-TR and SDH staining represent efficient methods for detecting senescent tumor cells in colorectal cancer.
    Keywords:  Cellular senescence; Colorectal neoplasms; Metabolism; NADH; Oxidative phosphorylation
    DOI:  https://doi.org/10.4132/jptm.2023.10.09
  23. Int J Cancer. 2023 Nov 10.
    Fast proliferating and slowly migrating non-small cell lung cancer cells are vulnerable to decitabine and retinoic acid combinatorial treatment.
    Giulia Pelos, Marisa Riester, Jagriti Pal, Ksenia Myacheva, Isabelle Moneke, John Charles Rotondo, Michael Lübbert, Sven Diederichs.
      Non-small cell lung cancer (NSCLC) patients are often elderly or unfit and thus cannot tolerate standard aggressive therapy regimes. In our study, we test the efficacy of the DNA-hypomethylating agent decitabine (DAC) in combination with all-trans retinoic acid (ATRA), which has been shown to possess little systemic adverse effects. Screening a broad panel of 56 NSCLC cell lines uncovered a decrease in cell viability after the combination treatment in 77% of the cell lines. Transcriptomics, proteomics, proliferation and migration profiling revealed that fast proliferating and slowly migrating cell lines were more sensitive to the drug combination. The comparison of mutational profiles found oncogenic KRAS mutations only in sensitive cells. Additionally, different cell lines showed a heterogeneous gene expression response to the treatment pointing to diverse mechanisms of action. Silencing KRAS, RIG-I or RARB partially reversed the sensitivity of KRAS-mutant NCI-H460 cells. To study resistance, we generated two NCI-H460 cell populations resistant to ATRA and DAC, which migrated faster and proliferated slower than the parental sensitive cells and showed signs of senescence. In summary, this comprehensive dataset uncovers a broad sensitivity of NSCLC cells to the combinatorial treatment with DAC and ATRA and indicates that migration and proliferation capacities correlate with and could thus serve as determinants for drug sensitivity in NSCLC.
    Keywords:  NCI-H460; NSCLC; drug resistance; epigenetic drugs; senescence
    DOI:  https://doi.org/10.1002/ijc.34783
  24. IET Syst Biol. 2023 Nov 08.
    Kinetic modelling of β-cell metabolism reveals control points in the insulin-regulating pyruvate cycling pathways.
    Rahul Rahul, Adam R Stinchcombe, Jamie W Joseph, Brian Ingalls.
      Insulin, a key hormone in the regulation of glucose homoeostasis, is secreted by pancreatic β-cells in response to elevated glucose levels. Insulin is released in a biphasic manner in response to glucose metabolism in β-cells. The first phase of insulin secretion is triggered by an increase in the ATP:ADP ratio; the second phase occurs in response to both a rise in ATP:ADP and other key metabolic signals, including a rise in the NADPH:NADP+ ratio. Experimental evidence indicates that pyruvate-cycling pathways play an important role in the elevation of the NADPH:NADP+ ratio in response to glucose. The authors developed a kinetic model for the tricarboxylic acid cycle and pyruvate cycling pathways. The authors successfully validated the model against experimental observations and performed a sensitivity analysis to identify key regulatory interactions in the system. The model predicts that the dicarboxylate carrier and the pyruvate transporter are the most important regulators of pyruvate cycling and NADPH production. In contrast, the analysis showed that variation in the pyruvate carboxylase flux was compensated by a response in the activity of mitochondrial isocitrate dehydrogenase (ICDm ) resulting in minimal effect on overall pyruvate cycling flux. The model predictions suggest starting points for further experimental investigation, as well as potential drug targets for the treatment of type 2 diabetes.
    Keywords:  beta-cell metabolism; global sensitivity analysis; mathematical model; type 2 diabetes
    DOI:  https://doi.org/10.1049/syb2.12077
  25. J Biomed Mater Res A. 2023 Nov 05.
    Establishment of a tissue-engineered colon cancer model for comparative analysis of cancer cell lines.
    Iman Hassani, Benjamin Anbiah, Andrew L Moore, Peter T Abraham, Ifeoluwa A Odeniyi, Nicole L Habbit, Michael W Greene, Elizabeth A Lipke.
      To overcome the limitations of in vitro two-dimensional (2D) cancer models in mimicking the complexities of the native tumor milieu, three-dimensional (3D) engineered cancer models using biomimetic materials have been introduced to more closely recapitulate the key attributes of the tumor microenvironment. Specifically, for colorectal cancer (CRC), a few studies have developed 3D engineered tumor models to investigate cell-cell interactions or efficacy of anti-cancer drugs. However, recapitulation of CRC cell line phenotypic differences within a 3D engineered matrix has not been systematically investigated. Here, we developed an in vitro 3D engineered CRC (3D-eCRC) tissue model using the natural-synthetic hybrid biomaterial PEG-fibrinogen and three CRC cell lines, HCT 116, HT-29, and SW480. To better recapitulate native tumor conditions, our 3D-eCRC model supported higher cell density encapsulation (20 × 106  cells/mL) and enabled longer term maintenance (29 days) as compared to previously reported in vitro CRC models. The 3D-eCRCs formed using each cell line demonstrated line-dependent differences in cellular and tissue properties, including cellular growth and morphology, cell subpopulations, cell size, cell granularity, migration patterns, tissue growth, gene expression, and tissue stiffness. Importantly, these differences were found to be most prominent from Day 22 to Day 29, thereby indicating the importance of long-term culture of engineered CRC tissues for recapitulation and investigation of mechanistic differences and drug response. Our 3D-eCRC tissue model showed high potential for supporting future in vitro comparative studies of disease progression, metastatic mechanisms, and anti-cancer drug candidate response in a CRC cell line-dependent manner.
    Keywords:  HCT 116; HT-29; PEG-fibrinogen; SW480; cancer tissue engineering; colorectal cancer
    DOI:  https://doi.org/10.1002/jbm.a.37611
  26. Nat Metab. 2023 Nov 09.
    Vitamin B5 supports MYC oncogenic metabolism and tumor progression in breast cancer.
    CRUK Rosetta Grand Challenge Consortium
      Tumors are intrinsically heterogeneous and it is well established that this directs their evolution, hinders their classification and frustrates therapy1-3. Consequently, spatially resolved omics-level analyses are gaining traction4-9. Despite considerable therapeutic interest, tumor metabolism has been lagging behind this development and there is a paucity of data regarding its spatial organization. To address this shortcoming, we set out to study the local metabolic effects of the oncogene c-MYC, a pleiotropic transcription factor that accumulates with tumor progression and influences metabolism10,11. Through correlative mass spectrometry imaging, we show that pantothenic acid (vitamin B5) associates with MYC-high areas within both human and murine mammary tumors, where its conversion to coenzyme A fuels Krebs cycle activity. Mechanistically, we show that this is accomplished by MYC-mediated upregulation of its multivitamin transporter SLC5A6. Notably, we show that SLC5A6 over-expression alone can induce increased cell growth and a shift toward biosynthesis, whereas conversely, dietary restriction of pantothenic acid leads to a reversal of many MYC-mediated metabolic changes and results in hampered tumor growth. Our work thus establishes the availability of vitamins and cofactors as a potential bottleneck in tumor progression, which can be exploited therapeutically. Overall, we show that a spatial understanding of local metabolism facilitates the identification of clinically relevant, tractable metabolic targets.
    DOI:  https://doi.org/10.1038/s42255-023-00915-7
  27. Cells. 2023 Oct 29. pii: 2539. [Epub ahead of print]12(21):
    A Subset of Colon Cancer Cell Lines Displays a Cytokine Profile Linked to Angiogenesis, EMT and Invasion Which Is Modulated by the Culture Conditions In Vitro.
    Jacqueline Bersano, Kanstantsin Lashuk, Anna Edinger, Julia Schueler.
      Colorectal cancer (CRC) is one of the deadliest cancers worldwide. The dysregulation of secretory pathways is a crucial driver of CRC progression, since it modulates cell proliferation, angiogenesis and survival. This study explores the changes in the CRC cytokine profile depending on the culture conditions and the presence of fibroblasts and macrophages as cellular components of the tumor microenvironment in 2D and in 3D formed spheroids. Upon analysis of 45 different cytokines, chemokines and growth factors, 20 CRC cell lines were categorized into high and low secretors. In the high secretor group cytokines related to angiogenesis, EMT and invasion were significantly upregulated. LIF and HFG were identified as the best discriminator between both groups. Independent of this grouping, the addition of normal as well as cancer-associated fibroblasts had a similar impact on the cytokine profile by increasing the total amount of secreted cytokines in most of the investigated cell lines. In contrast, the differentiation and polarization of macrophages was modulated differently by normal vs. cancer-associated fibroblasts. In summary, we identified two groups of CRC cell lines that differ in their cytokine profile. The dependance of this profile was analyzed in detail-not only from the tumor cell line but as well from the culture condition in vitro. Key cytokines that discriminate the two groups were identified and their importance as promising biomarker candidates for CRC discussed.
    Keywords:  colorectal cancer; cytokine profile; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells12212539
  28. Mol Metab. 2023 Nov 08. pii: S2212-8778(23)00170-9. [Epub ahead of print] 101836
    IL-6/JAK2-dependent G6PD phosphorylation promotes nucleotide synthesis and supports tumor growth.
    Xuemei Qiu, Hongping Ye, Xiaofei Li, Dan Li, Lu Jiang, Rui Liu, Zhe Zhao, Dan He.
      Tumor cells hijack inflammatory mechanisms to promote their own growth. IL-6 is one of the major cytokines, and is frequently upregulated in tumors. The pentose phosphate pathway (PPP) generates the indispensable building blocks to produce various nucleotides. However, whether and how PPP is timely tuned in response to IL-6 to support tumor growth remains largely unknown. Here we show that the metabolic flux of PPP and enzymatic activity of glucose-6-phosphate dehydrogenase (G6PD) is rapidly induced under IL-6 treatment, without obvious changes in G6PD expression level. Mechanistically, Janus kinase 2 (JAK2) phosphorylates G6PD Y437 under IL-6 treatment, which accentuates G6PD enzymatic activity by promoting G6PD binding with its substrate G6P. Further, JAK2-dependent G6PD Y437 phosphorylation is required for IL-6-induced nucleotide biosynthesis and tumor cell proliferation, and is associated with the progression of oral squamous cell carcinoma. Our findings report a new mechanism implicated in the crosstalk between tumor cells and inflammatory microenvironment, by which JAK2-dependent activation of G6PD governs nucleotide synthesis to support tumor cell proliferation, thereby highlighting its value as a potential anti-tumor target.
    Keywords:  G6PD; JAK2; nucleotide metabolism; pentose phosphate pathway; tumorigenesis
    DOI:  https://doi.org/10.1016/j.molmet.2023.101836
  29. Exp Cell Res. 2023 Nov 06. pii: S0014-4827(23)00402-0. [Epub ahead of print] 113851
    Hypoxia promotes the growth and metastasis of ovarian cancer cells by suppressing ferroptosis via upregulating SLC2A12.
    Mingmei Li, Li Li, Xiaoxiao Cheng, Longyu Li, Kaijia Tu.
       BACKGROUND: Ovarian cancer has been a worldwide health burden for women and its progression is highly hypoxia-independent. Here, we investigated the exact mechanisms by which hypoxia contributes to the malignant progression of ovarian cancer.
    METHOD: MTT, transwell, colony formation, and scratch wound healing assays were carried out for cellular functions. The underlying mechanism by which hypoxia functions was explored by RNA-seq, enrichment analysis, western blotting, qRT-PCR, flow cytometry, ChIP, luciferase reporter, and ELISA. Finally, animal experiments including the xenograft model and tumor metastasis model were constructed to validate the role of SLC2A12 in vivo.
    RESULTS: Hypoxia treatment promoted the cell proliferation, mobility, and colony growth abilities of the two ovarian cancer cell lines HO-8910 and A2780. RNA-seq and enrichment analysis showed that SLC2A12 was hyper-expressed under hypoxia condition and it may be related to glutathione and lipid metabolism. Besides, the expression of SLC2A12 was negatively correlated with overall survival. Hypoxia suppressed ferroptosis by SLC2A12 because silencing SLC2A12 declined the cell viability of HO-8910 and A2780 cells under hypoxia conditions, while the ferroptosis inhibitor ferrostatin-1 (Fer-1) breached that result and upregulated the expression of glutathione peroxidase 4 (GPX4). Moreover, hypoxia increased the expression of hypoxia inducible factor 1 A (HIF-1A), and the accumulated HIF-1A binds to hypoxia inducible factor 1 B (HIF1B) to form HIF-1 complex, then promoted the binding of hypoxic response elements (HRE) to SLC2A12 promoter by HIF-1/HRE signal. Subsequently, SLC2A12 regulated glutathione metabolism and in turn inhibited ferroptosis. The animal experiments indicated that silencing SLC2A12 could significantly inhibit tumor growth and metastasis in vivo.
    CONCLUSION: Hypoxia promoted ovarian cancer progression by upregulating SLC2A12 and then regulating glutathione metabolism to inhibit ferroptosis.
    Keywords:  Ferroptosis; Glutathione metabolism; Hypoxia; SLC2A12; ovarian cancer
    DOI:  https://doi.org/10.1016/j.yexcr.2023.113851
  30. Int J Oncol. 2024 Jan;pii: 1. [Epub ahead of print]64(1):
    Endoplasmic reticulum regulation of glucose metabolism in glioma stem cells.
    María Turos-Cabal, Ana M Sánchez-Sánchez, Noelia Puente-Moncada, Federico Herrera, Jezabel Rodriguez-Blanco, Isaac Antolin, Marco Antonio Alvarez-Vega, Carmen Rodríguez, Vanesa Martín.
      Glioblastoma (GBM) treatment is extremely challenging due to the high complexity of the tumor. It is one of the tumors in which a subpopulation of highly resistant glioma initiating cells (GICs) has been clearly identified. Thus, understanding the differences between GICs and tumor bulk cells is therefore essential to move to less conventional but more efficient approaches. It was found that, unlike their differentiated progeny, GICs survival and maintenance of stem cell properties depend on mitochondrial metabolism. GICs present higher glucose uptake and mitochondrial membrane potential and reduced lactate dehydrogenase activity, being more sensitive to mitochondrial inhibition than their differentiated counterparts. Calcium flux to the mitochondria appears to play an essential role in the maintenance of this distinct metabolic phenotype with a decrease in the expression of voltage‑dependent anionic channel (VDAC) and Grp75, two of the proteins of the IP3R‑Grp75‑VDAC complex that transfers calcium from the endoplasmic reticulum (ER) to the mitochondria. Disruption of ER homeostasis using ER stress inducers or inhibition of ER‑mitochondrial contact sites using the Grp75 inhibitor MKT‑077 resulted in cytotoxicity of GICs and loss of stemness. Moreover, MKT‑077 also potentiates the effect of temozolomide, current treatment for glioblastoma. In summary, the present data indicated that ER‑mitochondrial homeostasis is essential for regulation of GICs glucose metabolism and survival.
    Keywords:  endoplasmic reticulum; glioma initiating cells; metabolic reprograming; mitochondria; mitochondria‑ER contact sites
    DOI:  https://doi.org/10.3892/ijo.2023.5589
  31. Biochem Pharmacol. 2023 Nov 04. pii: S0006-2952(23)00500-2. [Epub ahead of print] 115907
    Targeting cholesterol metabolism in Cancer: From molecular mechanisms to therapeutic implications.
    Jia Lu, Siwei Chen, Xuejiao Bai, Minru Liao, Yuling Qiu, Ling-Li Zheng, Haiyang Yu.
      Cholesterol is an essential component of cell membranes and helps to maintain their structure and function. Abnormal cholesterol metabolism has been linked to the development and progression of tumors. Changes in cholesterol metabolism triggered by internal or external stimuli can promote tumor growth. During metastasis, tumor cells require large amounts of cholesterol to support their growth and colonization of new organs. Recent research has shown that cholesterol metabolism is reprogrammed during tumor development, and this can also affect the anti-tumor activity of immune cells in the surrounding environment. However, identifying the specific targets in cholesterol metabolism that regulate cancer progression and the tumor microenvironment is still a challenge. Additionally, exploring the potential of combining statin drugs with other therapies for different types of cancer could be a worthwhile avenue for future drug development. In this review, we focus on the molecular mechanisms of cholesterol and its derivatives in cell metabolism and the tumor microenvironment, and discuss specific targets and relevant therapeutic agents that inhibit aspects of cholesterol homeostasis.
    Keywords:  Cancer; Cholesterol metabolism; Molecular mechanisms; Therapeutic agent; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bcp.2023.115907
  32. Lab Chip. 2023 Nov 09.
    Simple droplet microfluidics platform for drug screening on cancer spheroids.
    Caroline Parent, Kiran Raj Melayil, Ya Zhou, Vivian Aubert, Didier Surdez, Olivier Delattre, Claire Wilhelm, Jean-Louis Viovy.
      3D in vitro biological systems are progressively replacing 2D systems to increase the physiological relevance of cellular studies. Microfluidics-based approaches can be powerful tools towards such biomimetic systems, but often require high-end complicated and expensive processes and equipment for microfabrication. Herein, a drug screening platform is proposed, minimizing technicality and manufacturing steps. It provides an alternate way of spheroid generation in droplets in tubes. Droplet microfluidics then elicit multiple droplets merging events at programmable times, to submit sequentially the spheroids to chemotherapy and to reagents for cytotoxicity screening. After a comprehensive study of tumorogenesis within the droplets, the system is validated for drug screening (IC50) with chemotherapies in cancer cell lines as well as cells from a patient-derived-xenografts (PDX). As compared to microtiter plates methods, our system reduces the initial number of cells up to 10 times and opens new avenues towards primary tumors drug screening approaches.
    DOI:  https://doi.org/10.1039/d3lc00417a
  33. Anticancer Drugs. 2023 Nov 13.
    Dual targeting of Mcl-1 and Bcl-2 to overcome chemoresistance in cervical and colon cancer.
    Ling Wang, Changlei Xi, Rong Liu, Tingting Ye, Ning Xiang, Jinfang Deng, Hui Li.
      After an initial positive response to chemotherapy, cancer patients often become resistant and experience relapse. Our previous research identified eukaryotic translation initiation factor 4E (eIF4E) as a crucial target to overcome chemoresistance. In this study, we delved further into the role and therapeutic potential of myeloid cell leukemia 1 (Mcl-1), an eIF4E-mediated target, in chemoresistance. We showed that the levels of phosphor and total eIF4E, as well as Mcl-1, were elevated in chemoresistant cervical but not colon cancer cells. Mcl-1 inhibitor S64315 decreased Mcl-1 levels in chemoresistant cancer cells, regardless of Mcl-1 upregulation, decreased viability in chemoresistant cancer cells and acted synergistically with chemotherapy drugs. The combined inhibition of Mcl-1 and B-cell lymphoma 2 (Bcl-2), employing both genetic and pharmacological approaches, led to a markedly more substantial decrease in viability compared with the inhibition of either target individually. The combination of S64315 and Bcl-2 inhibitors reduced tumor growth in chemoresistant cervical and colon cancer models without causing general toxicity in mice. This combination also prolonged overall survival compared with using S64315 or venetoclax alone. Our research highlights the therapeutic potential of inhibiting Mcl-1 and Bcl-2 simultaneously in chemoresistant cancers and provides a rationale for initiating clinical trials to investigate the combination of S64315 and venetoclax for the treatment of advanced colon and cervical cancer.
    DOI:  https://doi.org/10.1097/CAD.0000000000001553
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