bims-medica Biomed News
on Metabolism and diet in cancer
Issue of 2023–12–31
seventeen papers selected by
Brett Chrest, East Carolina University
  1. Induction of Fatty Acid Oxidation Underlies DNA Damage-Induced Cell Death and Ameliorates Obesity-Driven Chemoresistance.
  2. Cyclin D1 extensively reprograms metabolism to support biosynthetic pathways in hepatocytes.
  3. Mitochondrion: Main organelle in orchestrating cancer escape from chemotherapy.
  4. Mitochondrial regulation of GPX4 inhibition-mediated ferroptosis in acute myeloid leukemia.
  5. Metabolomics at the tumor microenvironment interface: Decoding cellular conversations.
  6. Nutrition and dietary restrictions in cancer prevention.
  7. Real-time monitoring of glucose metabolism and effects of metformin on HepG2 cells using 13C in-cell NMR spectroscopy.
  8. Suppression of the KRAS-NRF2 axis shifts arginine into the phosphocreatine energy system in pancreatic cancer cells.
  9. High and low dietary fiber consumption and cancer risk: a comprehensive umbrella review with meta-meta-analysis involving meta-analyses of observational epidemiological studies.
  10. Nutritional Therapy Strategies Targeting Tumor Energy Metabolism.
  11. Glutathione depletion and dihydroorotate dehydrogenase inhibition actuated ferroptosis-augment to surmount triple-negative breast cancer.
  12. A long-term ketogenic diet in young and aged rats has dissociable effects on prelimbic cortex and CA3 ensemble activity.
  13. Distinct lactate metabolism between hepatocytes and myotubes revealed by live cell imaging with genetically encoded indicators.
  14. [11C] Methionine-PET Imaging as a Cancer Biomarker for Methionine Addiction and Sensitivity to Methionine-restriction-based Combination Chemotherapy.
  15. Microfluidic devices for precise measurements of cell directionality reveal a role for glutamine during cell migration.
  16. UBC9 stabilizes PFKFB3 to promote aerobic glycolysis and proliferation of glioblastoma cells.
  17. Effects of Ketogenic Diet Intervention on Metabolic Acidosis in Patients with Obesity and Chronic Kidney Disease.
  1. Adv Sci (Weinh). 2023 Dec 25. e2304702
    Induction of Fatty Acid Oxidation Underlies DNA Damage-Induced Cell Death and Ameliorates Obesity-Driven Chemoresistance.
    Sunsook Hwang, Seungyeon Yang, Kyungsoo Park, Byungjoo Kim, Minjoong Kim, Seungmin Shin, Ahyoung Yoo, Jiyun Ahn, Juneil Jang, Yeong Shin Yim, Rho H Seong, Seung Min Jeong.
      The DNA damage response is essential for preserving genome integrity and eliminating damaged cells. Although cellular metabolism plays a central role in cell fate decision between proliferation, survival, or death, the metabolic response to DNA damage remains largely obscure. Here, this work shows that DNA damage induces fatty acid oxidation (FAO), which is required for DNA damage-induced cell death. Mechanistically, FAO induction increases cellular acetyl-CoA levels and promotes N-alpha-acetylation of caspase-2, leading to cell death. Whereas chemotherapy increases FAO related genes through peroxisome proliferator-activated receptor α (PPARα), accelerated hypoxia-inducible factor-1α stabilization by tumor cells in obese mice impedes the upregulation of FAO, which contributes to its chemoresistance. Finally, this work finds that improving FAO by PPARα activation ameliorates obesity-driven chemoresistance and enhances the outcomes of chemotherapy in obese mice. These findings reveal the shift toward FAO induction is an important metabolic response to DNA damage and may provide effective therapeutic strategies for cancer patients with obesity.
    Keywords:  DNA damage; cell death; chemoresistance; fatty acid oxidation; obesity
    DOI:  https://doi.org/10.1002/advs.202304702
  2. J Biol Chem. 2023 Dec;pii: S0021-9258(23)02435-3. [Epub ahead of print]299(12): 105407
    Cyclin D1 extensively reprograms metabolism to support biosynthetic pathways in hepatocytes.
    Heng Wu, Betsy T Kren, Andrew N Lane, Teresa A Cassel, Richard M Higashi, Teresa W M Fan, George S Scaria, Laurie L Shekels, Mark A Klein, Jeffrey H Albrecht.
      Cell proliferation requires metabolic reprogramming to accommodate biosynthesis of new cell components, and similar alterations occur in cancer cells. However, the mechanisms linking the cell cycle machinery to metabolism are not well defined. Cyclin D1, along with its main partner cyclin-dependent kinase 4 (Cdk4), is a pivotal cell cycle regulator and driver oncogene that is overexpressed in many cancers. Here, we examine hepatocyte proliferation to define novel effects of cyclin D1 on biosynthetic metabolism. Metabolomic studies reveal that cyclin D1 broadly promotes biosynthetic pathways including glycolysis, the pentose phosphate pathway, and the purine and pyrimidine nucleotide synthesis in hepatocytes. Proteomic analyses demonstrate that overexpressed cyclin D1 binds to numerous metabolic enzymes including those involved in glycolysis and pyrimidine synthesis. In the glycolysis pathway, cyclin D1 activates aldolase and GAPDH, and these proteins are phosphorylated by cyclin D1/Cdk4 in vitro. De novo pyrimidine synthesis is particularly dependent on cyclin D1. Cyclin D1/Cdk4 phosphorylates the initial enzyme of this pathway, carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), and metabolomic analysis indicates that cyclin D1 depletion markedly reduces the activity of this enzyme. Pharmacologic inhibition of Cdk4 along with the downstream pyrimidine synthesis enzyme dihydroorotate dehydrogenase synergistically inhibits proliferation and survival of hepatocellular carcinoma cells. These studies demonstrate that cyclin D1 promotes a broad network of biosynthetic pathways in hepatocytes, and this model may provide insights into potential metabolic vulnerabilities in cancer cells.
    Keywords:  BAY 2402234; aldolase; anaerobic glycolysis; cell cycle; cyclin D1; glyceraldehyde-3-phosphate dehydrogenase (GAPDH); liver regeneration; palbociclib; pentose phosphate pathway (PPP); purine; pyrimidine
    DOI:  https://doi.org/10.1016/j.jbc.2023.105407
  3. Cancer Rep (Hoboken). 2023 Dec 27. e1942
    Mitochondrion: Main organelle in orchestrating cancer escape from chemotherapy.
    Samaneh Mostafavi, Nahid Eskandari.
       BACKGROUND: Chemoresistance is a challenging barrier to cancer therapy, and in this context, the role of mitochondria is significant. We put emphasis on key biological characteristics of mitochondria, contributing to tumor escape from various therapies, to find the "Achilles' Heel" of cancer cells for future drug design.
    RECENT FINDINGS: The mitochondrion is a dynamic organelle, and its existence is important for tumor growth. Its metabolites also cooperate with cell signaling in tumor proliferation and drug resistance.
    CONCLUSION: Biological characteristics of this organelle, such as redox balance, DNA depletion, and metabolic reprogramming, provide flexibility to cancer cells to cope with therapy-induced stress.
    Keywords:  drug resistance; mitochondria; neoplasm; oxidation-reduction
    DOI:  https://doi.org/10.1002/cnr2.1942
  4. Leukemia. 2023 Dec 26.
    Mitochondrial regulation of GPX4 inhibition-mediated ferroptosis in acute myeloid leukemia.
    Hiroki Akiyama, Ran Zhao, Lauren B Ostermann, Ziyi Li, Matthew Tcheng, Samar J Yazdani, Arman Moayed, Malcolm L Pryor, Sandeep Slngh, Natalia Baran, Edward Ayoub, Yuki Nishida, Po Yee Mak, Vivian R Ruvolo, Bing Z Carter, Aaron D Schimmer, Michael Andreeff, Jo Ishizawa.
      Resistance to apoptosis in acute myeloid leukemia (AML) cells causes refractory or relapsed disease, associated with dismal clinical outcomes. Ferroptosis, a mode of non-apoptotic cell death triggered by iron-dependent lipid peroxidation, has been investigated as potential therapeutic modality against therapy-resistant cancers, but our knowledge of its role in AML is limited. We investigated ferroptosis in AML cells and identified its mitochondrial regulation as a therapeutic vulnerability. GPX4 knockdown induced ferroptosis in AML cells, accompanied with characteristic mitochondrial lipid peroxidation, exerting anti-AML effects in vitro and in vivo. Electron transport chains (ETC) are primary sources of coenzyme Q10 (CoQ) recycling for its function of anti-lipid peroxidation in mitochondria. We found that the mitochondria-specific CoQ potently inhibited GPX4 inhibition-mediated ferroptosis, suggesting that mitochondrial lipid redox regulates ferroptosis in AML cells. Consistently, Rho0 cells, which lack functional ETC, were more sensitive to GPX4 inhibition-mediated mitochondrial lipid peroxidation and ferroptosis than control cells. Furthermore, degradation of ETC through hyperactivation of a mitochondrial protease, caseinolytic protease P (ClpP), synergistically enhanced the anti-AML effects of GPX4 inhibition. Collectively, our findings indicate that in AML cells, GPX4 inhibition induces ferroptosis, which is regulated by mitochondrial lipid redox and ETC.
    DOI:  https://doi.org/10.1038/s41375-023-02117-2
  5. Med Res Rev. 2023 Dec 26.
    Metabolomics at the tumor microenvironment interface: Decoding cellular conversations.
    Naomi Berrell, Habib Sadeghirad, Tony Blick, Charles Bidgood, Graham R Leggatt, Ken O'Byrne, Arutha Kulasinghe.
      Cancer heterogeneity remains a significant challenge for effective cancer treatments. Altered energetics is one of the hallmarks of cancer and influences tumor growth and drug resistance. Studies have shown that heterogeneity exists within the metabolic profile of tumors, and personalized-combination therapy with relevant metabolic interventions could improve patient response. Metabolomic studies are identifying novel biomarkers and therapeutic targets that have improved treatment response. The spatial location of elements in the tumor microenvironment are becoming increasingly important for understanding disease progression. The evolution of spatial metabolomics analysis now allows scientists to deeply understand how metabolite distribution contributes to cancer biology. Recently, these techniques have spatially resolved metabolite distribution to a subcellular level. It has been proposed that metabolite mapping could improve patient outcomes by improving precision medicine, enabling earlier diagnosis and intraoperatively identifying tumor margins. This review will discuss how altered metabolic pathways contribute to cancer progression and drug resistance and will explore the current capabilities of spatial metabolomics technologies and how these could be integrated into clinical practice to improve patient outcomes.
    Keywords:  cancer metabolism; glucose; immunotherapy; metabolic interventions; spatial biology
    DOI:  https://doi.org/10.1002/med.22010
  6. Biochim Biophys Acta Rev Cancer. 2023 Dec 24. pii: S0304-419X(23)00212-3. [Epub ahead of print] 189063
    Nutrition and dietary restrictions in cancer prevention.
    Amrendra Mishra, Giacomo Giuliani, Valter D Longo.
      The composition and pattern of dietary intake have emerged as key factors influencing aging, regeneration, and consequently, healthspan and lifespan. Cancer is one of the major diseases more tightly linked with aging, and age-related mortality. Although the role of nutrition in cancer incidence is generally well established, we are far from a consensus on how diet influences tumour development in different tissues. In this review, we will discuss how diet and dietary restrictions affect cancer risk and the molecular mechanisms potentially responsible for their effects. We will cover calorie restriction, intermittent fasting, prolonged fasting, fasting-mimicking diet, time-restricted eating, ketogenic diet, high protein diet, Mediterranean diet, and the vegan and vegetarian diets.
    Keywords:  Calorie restriction; Cancer prevention; Dietary restrictions; Fasting mimicking diet; Intermittent fasting; Mediterranean diet
    DOI:  https://doi.org/10.1016/j.bbcan.2023.189063
  7. Biochem Biophys Res Commun. 2023 Dec 19. pii: S0006-291X(23)01477-8. [Epub ahead of print]694 149383
    Real-time monitoring of glucose metabolism and effects of metformin on HepG2 cells using 13C in-cell NMR spectroscopy.
    Muzhou Teng, Zhijia Li, Yanmei Gu, Yitao Fan, Daijun Wang, Meiyu Liu, Yumin Li, Gang Wei, Yanjie Huang.
      Metformin is currently a strong candidate antitumor agent for multiple cancers, and has the potential to inhibit cancer cell viability, growth, and proliferation. Metabolic reprogramming is a critical feature of cancer cells. However, the effects of metformin which targets glucose metabolism on HepG2 cancer cells remain unclear. In this study, to explore the effects of metformin on glucose metabolism in HepG2 cells, we conducted real-time metabolomic monitoring of live HepG2 cells treated with metformin using 13C in-cell NMR spectroscopy. Metabolic tracing with U-13C6-glucose revealed that metformin significantly increased the production of 13C-G3P and 13C-glycerol, which were reported to attenuate liver cancer development, but decreased the production of potential oncogenesis-supportive metabolites, including 13C-lactate, 13C-alanine, 13C-glycine, and 13C-glutamate. Moreover, the expression levels of enzymes associated with the measured metabolites were carried out. The results showed that the levels of ALT1, MCT4, GPD2 and MPC1 were greatly reduced, which were consistent with the changes of measured metabolites in 13C in-cell NMR spectroscopy. Overall, our approach directly provides fundamental insights into the effects of metformin on glucose metabolism in live HepG2 cells, and highlights the potential mechanism of metformin, including the increase in production of G3P and glycerol derived from glucose, as well as the inhibition of glucose incorporation into lactate, alanine, glutamate, and glycine.
    Keywords:  Glutamate excretion; Glycerol metabolism; Glycine metabolism
    DOI:  https://doi.org/10.1016/j.bbrc.2023.149383
  8. iScience. 2023 Dec 15. 26(12): 108566
    Suppression of the KRAS-NRF2 axis shifts arginine into the phosphocreatine energy system in pancreatic cancer cells.
    Eros Di Giorgio, Himanshi Choudhary, Annalisa Ferino, Ylenia Cortolezzis, Emiliano Dalla, Francesca D'Este, Marina Comelli, Valentina Rapozzi, Luigi E Xodo.
      In pancreatic ductal adenocarcinomas (PDAC), the KRASG12D-NRF2 axis controls cellular functions such as redox homeostasis and metabolism. Disruption of this axis through suppression of NRF2 leads to profound reprogramming of metabolism. Unbiased transcriptome and metabolome analyses showed that PDAC cells with disrupted KRASG12D-NRF2 signaling (NRF2-/- cells) shift from aerobic glycolysis to metabolic pathways fed by amino acids. Metabolome, RNA-seq and qRT-PCR analyses revealed a blockade of the urea cycle, making NRF2-/- cells dependent on exogenous arginine for survival. Arginine is channeled into anabolic pathways, including the synthesis of phosphocreatine, which generates an energy buffer essential for cell growth. A similar switch was observed in tumor clones that had survived FOLFIRINOX therapy or blockade of KRAS signaling. Inhibition of the creatine pathway with cyclocreatine reduced both ATP and invasion rate in 3D spheroids from NRF2-deficient PDAC cells. Our study provides basis for the rational development of combination therapies for pancreatic cancer.
    Keywords:  Cancer; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2023.108566
  9. Crit Rev Food Sci Nutr. 2023 Dec 28. 1-14
    High and low dietary fiber consumption and cancer risk: a comprehensive umbrella review with meta-meta-analysis involving meta-analyses of observational epidemiological studies.
    Mehmet Emin Arayici, Yasemin Basbinar, Hulya Ellidokuz.
      It is a well-known fact that dietary fiber is recognized as one of the essential components of a healthy diet. The aim of this paper was to investigate the impact of dietary fiber on the incidence and mortality of various types of cancer, the current evidence in this field, and the biases of this evidence using the meta-meta-analysis method. We identified meta-analyses that particularly focused on the association between dietary fiber consumption and the risk/mortality of cancer. A structured and comprehensive computer literature search was undertaken in the electronic databases PubMed/Medline, Web of Science (WoS), and Scopus. The search yielded a total of 25 papers and 28 reports. In the pooled analysis, higher dietary fiber consumption was associated with a 22% lower cancer risk (OR = 0.78, 95% CI: 0.74-0.83, p < 0.001) and a 17% lower mortality (RR = 0.83, 95% CI: 0.78-0.90, p < 0.001). In the secondary meta-meta-analysis, it was observed that there was an inverse association between dietary fiber intake and digestive tract cancers (OR = 0.68, 95% CI: 0.62-0.76) and breast cancer (OR = 0.92, 95% CI: 0.90-0.94). Taken together, this paper suggests that promoting a high-fiber diet may be an effective strategy for the prevention and management of cancer.
    Keywords:  Cancer; dietary fiber; incidence; meta-analysis; mortality
    DOI:  https://doi.org/10.1080/10408398.2023.2298772
  10. Curr Drug Metab. 2023 Dec 28.
    Nutritional Therapy Strategies Targeting Tumor Energy Metabolism.
    Taojia Chen, Haining Yu.
      Cancer is the second leading cause of mortality worldwide. The heightened nutrient uptake, particularly glucose, and elevated glycolysis observed in rapidly proliferating tumor cells highlight the potential targeting of energy metabolism pathways for the treatment of cancer. Numerous studies and clinical trials have demonstrated the efficacy of nutritional therapy in mitigating the adverse effects of chemotherapy and radiotherapy, enhancing treatment outcomes, prolonging survival, and improving the overall quality of life of patients. This review article comprehensively examines nutritional therapy strategies that specifically address tumor energy metabolism. Moreover, it explores the intricate interplay between energy metabolism and the gut microbiota in the context of nutritional therapy. The findings aim to provide valuable insights for future clinical research endeavors in this field.
    Keywords:  Tumor; cancer treatment; energy metabolism; glucose.; mitochondria; nutritional therapy
    DOI:  https://doi.org/10.2174/0113892002280203231213110634
  11. Biomaterials. 2023 Dec 26. pii: S0142-9612(23)00455-6. [Epub ahead of print]305 122447
    Glutathione depletion and dihydroorotate dehydrogenase inhibition actuated ferroptosis-augment to surmount triple-negative breast cancer.
    Tian-Jiao Zhou, Meng-Meng Zhang, Dan-Meng Liu, Li-Ling Huang, Hai-Qing Yu, Yi Wang, Lei Xing, Hu-Lin Jiang.
      Ferroptosis is a promising therapeutic approach for combating malignant cancers, but its effectiveness is limited in clinical due to the adaptability and self-repair abilities of cancer cells. Mitochondria, as the pivotal player in ferroptosis, exhibit tremendous therapeutic potential by targeting the intramitochondrial anti-ferroptotic pathway mediated by dihydroorotate dehydrogenase (DHODH). In this study, an albumin-based nanomedicine was developed to induce augmented ferroptosis in triple-negative breast cancer (TNBC) by depleting glutathione (GSH) and inhibiting DHODH activity. The nanomedicine (ATO/SRF@BSA) was developed by loading sorafenib (SRF) and atovaquone (ATO) into bovine serum albumin (BSA). SRF is an FDA-approved ferroptosis inducer and ATO is the only drug used in clinical that targets mitochondria. By combining the effects of SRF and ATO, ATO/SRF@BSA promoted the accumulation of lipid peroxides within mitochondria by inhibiting the glutathione peroxidase 4 (GPX4)-GSH pathway and downregulating the DHODH-coenzyme Q (CoQH2) defense mechanism, triggers a burst of lipid peroxides. Simultaneously, ATO/SRF@BSA suppressed cancer cell self-repair and enhanced cell death by inhibiting the synthesis of adenosine triphosphate (ATP) and pyrimidine nucleotides. Furthermore, the anti-cancer results showed that ATO/SRF@BSA exhibited tumor-specific killing efficacy, significantly improved the tumor hypoxic microenvironment, and lessened the toxic side effects of SRF. This work presents an efficient and easily achievable strategy for TNBC treatment, which may hold promise for clinical applications.
    Keywords:  Atovaquone; Ferroptosis; Lipid peroxides; Mitochondrion; Triple-negative breast cancer
    DOI:  https://doi.org/10.1016/j.biomaterials.2023.122447
  12. Front Aging Neurosci. 2023 ;15 1274624
    A long-term ketogenic diet in young and aged rats has dissociable effects on prelimbic cortex and CA3 ensemble activity.
    Abbi R Hernandez, Maya E Barrett, Katelyn N Lubke, Andrew P Maurer, Sara N Burke.
       Introduction: Age-related cognitive decline has been linked to distinct patterns of cellular dysfunction in the prelimbic cortex (PL) and the CA3 subregion of the hippocampus. Because higher cognitive functions require both structures, selectively targeting a neurobiological change in one region, at the expense of the other, is not likely to restore normal behavior in older animals. One change with age that both the PL and CA3 share, however, is a reduced ability to utilize glucose, which can produce aberrant neural activity patterns.
    Methods: The current study used a ketogenic diet (KD) intervention, which reduces the brain's reliance on glucose, and has been shown to improve cognition, as a metabolic treatment for restoring neural ensemble dynamics in aged rats. Expression of the immediate-early genes Arc and Homer1a were used to quantify the neural ensembles that were active in the home cage prior to behavior, during a working memory/biconditional association task, and a continuous spatial alternation task.
    Results: Aged rats on the control diet had increased activity in CA3 and less ensemble overlap in PL between different task conditions than did the young animals. In the PL, the KD was associated with increased activation of neurons in the superficial cortical layers, establishing a clear link between dietary macronutrient content and frontal cortical activity. The KD did not lead to any significant changes in CA3 activity.
    Discussion: These observations suggest that the availability of ketone bodies may permit the engagement of compensatory mechanisms in the frontal cortices that produce better cognitive outcomes.
    Keywords:  Arc; Homer; aging; behavior; ketosis
    DOI:  https://doi.org/10.3389/fnagi.2023.1274624
  13. Biochem Biophys Res Commun. 2023 Dec 20. pii: S0006-291X(23)01510-3. [Epub ahead of print]694 149416
    Distinct lactate metabolism between hepatocytes and myotubes revealed by live cell imaging with genetically encoded indicators.
    Mina Horikoshi, Kazuki Harada, Saki Tsuno, Tetsuya Kitaguchi, Masami Yokota Hirai, Mitsuharu Matsumoto, Shin Terada, Takashi Tsuboi.
      The process of glycolysis breaks down glycogen stored in muscles, producing lactate through pyruvate to generate energy. Excess lactate is then released into the bloodstream. When lactate reaches the liver, it is converted to glucose, which muscles utilize as a substrate to generate ATP. Although the biochemical study of lactate metabolism in hepatocytes and skeletal muscle cells has been extensive, the spatial and temporal dynamics of this metabolism in live cells are still unknown. We observed the dynamics of metabolism-related molecules in primary cultured hepatocytes and a skeletal muscle cell line upon lactate overload. Our observations revealed an increase in cytoplasmic pyruvate concentration in hepatocytes, which led to glucose release. Skeletal muscle cells exhibited elevated levels of lactate and pyruvate levels in both the cytoplasm and mitochondrial matrix. However, mitochondrial ATP levels remained unaffected, indicating that the increased lactate can be converted to pyruvate but is unlikely to be utilized for ATP production. The findings suggest that excess lactate in skeletal muscle cells is taken up into mitochondria with little contribution to ATP production. Meanwhile, lactate released into the bloodstream can be converted to glucose in hepatocytes for subsequent utilization in skeletal muscle cells.
    Keywords:  Cori cycle; Hepatocytes; L6 cells; Lactate metabolism; Live cell imaging
    DOI:  https://doi.org/10.1016/j.bbrc.2023.149416
  14. In Vivo. 2024 Jan-Feb;38(1):38(1): 253-258
    [11C] Methionine-PET Imaging as a Cancer Biomarker for Methionine Addiction and Sensitivity to Methionine-restriction-based Combination Chemotherapy.
    Yutaro Kubota, Toshihiko Sato, Qinghong Han, Chihiro Hozumi, Sei Morinaga, Kohei Mizuta, Takuya Tsunoda, Robert M Hoffman.
       BACKGROUND/AIM: Methionine addiction is a fundamental and universal hallmark of cancer, termed the Hoffman effect. Methionine addiction of cancer is greater than glucose addiction, termed the Warburg effect, as shown by the comparison of PET imaging with [11C]methionine and [18F]fluorodeoxyglucose. The aim of the present study was to determine whether [11C]methionine PET (MET-PET) images could be a biomarker of methionine addiction of cancer and potential response to methionine-restriction-based combination chemotherapy.
    PATIENTS AND METHODS: In the present study a patient with invasive lobular carcinoma of the breast metastatic to axillary lymph nodes was imaged by both MET-PET and [18F]fluorodeoxyglucose PET (FDG-PET) before and after combination treatment with methionine restriction, comprising a low-methionine diet and methioninase, along with first-line chemotherapy.
    RESULTS: MET-PET gave a much stronger and precise image of the patient's metastatic axillary lymph nodes than FDG-PET. The patient had a complete response to methionine restriction-based chemotherapy as shown by MET-PET.
    CONCLUSION: MET-PET imaging is a biomarker of methionine-addicted cancer and potential response to methionine-restriction-based chemotherapy.
    Keywords:  Cancer; Hoffman effect; PET imaging; [11C]methionine; chemotherapy; combination; methioninase; methionine addiction; methionine restriction
    DOI:  https://doi.org/10.21873/invivo.13432
  15. Sci Rep. 2023 Dec 27. 13(1): 23032
    Microfluidic devices for precise measurements of cell directionality reveal a role for glutamine during cell migration.
    Nil Gural, Daniel Irimia.
      Cancer cells that migrate from tumors into surrounding tissues are responsible for cancer dissemination through the body. Microfluidic devices have been instrumental in discovering unexpected features of cancer cell migration, including the migration in self-generated gradients and the contributions of cell-cell contact during collective migration. Here, we design microfluidic channels with five successive bifurcations to characterize the directionality of cancer cell migration with high precision. We uncover an unexpected role for glutamine in epithelial cancer cell orientation, which could be replaced by alfa-keto glutarate but not glucose.
    DOI:  https://doi.org/10.1038/s41598-023-49866-9
  16. Int J Biochem Cell Biol. 2023 Dec;pii: S1357-2725(23)00130-9. [Epub ahead of print]165 106491
    UBC9 stabilizes PFKFB3 to promote aerobic glycolysis and proliferation of glioblastoma cells.
    Zhaoyuan Meng, Xueli Bian, Leina Ma, Gang Zhang, Qingxia Ma, Qianqian Xu, Juanjuan Liu, Runze Wang, Jie Lun, Qian Lin, Gaoxiang Zhao, Hongfei Jiang, Wensheng Qiu, Jing Fang, Zhimin Lu.
      Cancer cells prefer to utilizing aerobic glycolysis to generate energy and anabolic metabolic intermediates for cell growth. However, whether the activities of glycolytic enzymes can be regulated by specific posttranslational modifications, such as SUMOylation, in response to oncogenic signallings, thereby promoting the Warburg effect, remain largely unclear. Here, we demonstrate that phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a key glycolytic enzyme, interacts with SUMO-conjugating enzyme UBC9 and is SUMOylated at K302 in glioblastoma cells. Expression of UBC9, which competitively prevents the binding of ubiquitin E3 ligase APC/C to PFKFB3 and subsequent PFKFB3 polyubiquitination, increases PFKFB3 stability and expression. Importantly, EGFR activation increases the interaction between UBC9 and PFKFB3, leading to increased SUMOylation and expression of PFKFB3. This increase is blocked by inhibition of EGFR-induced AKT activation whereas expression of activate AKT by itself was sufficient to recapitulate EGF-induced effect. Knockout of PFKFB3 expression decreases EGF-enhanced lactate production and GBM cell proliferation and this decrease was fully rescued by reconstituted expression of WT PFKFB3 whereas PFKFB3 K302R mutant expression abrogates EGF- and UBC9-regulated lactate production and GBM cell proliferation. These findings reveal a previously unknown mechanism underlying the regulation of the Warburg effect through the EGFR activation-induced and UBC9-mediated SUMOylation and stabilization of PFKFB3.
    Keywords:  Glioma; Glycolysis; PFKFB3; SUMOylation; UBC9
    DOI:  https://doi.org/10.1016/j.biocel.2023.106491
  17. Mo Med. 2023 Nov-Dec;120(6):120(6): 451-458
    Effects of Ketogenic Diet Intervention on Metabolic Acidosis in Patients with Obesity and Chronic Kidney Disease.
    Reuben J R De Almeida, Fouad Jaber, Rawan Rajab, Mallak Zatreh, Peminda Cabandugama, Nada Bader.
      In this study, we found no significant acid-base changes after six weeks of ketogenic diet in patients with obesity with Chronic kidney disease) 2 or 3. A ketogenic diet was well tolerated overall with no gross changes to serum creatinine, anion gap, serum, or venous bicarbonate, or albumin. We were limited by a small sample size, and we did not confirm whether patients achieved a biochemical ketogenic state.
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