bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2022–09–11
twenty papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. GLS1 is a protective factor in patients with ovarian clear cell carcinoma and its expression does not correlate with ARID1A-mutated tumors.
  2. Hormone-Glutamine Metabolism: A Critical Regulatory Axis in Endocrine-Related Cancers.
  3. Metabolic management of microenvironment acidity in glioblastoma.
  4. The roles of glycolysis in osteosarcoma.
  5. Targeting Glutaminolysis to treat Multiple Myeloma: An In Vitro Evaluation of Glutaminase Inhibitors Telaglenastat and Epigallocatechin-3-gallate.
  6. An optimized method for estimating glutaminase activity in biological samples.
  7. Small leucine zipper protein functions as a modulator for metabolic reprogramming of colorectal cancer cells by inducing nutrient stress-mediated autophagy.
  8. Multiple myeloma metabolism - a treasure trove of therapeutic targets?
  9. Structural aspects of the glucose and monocarboxylate transporters involved in the Warburg effect.
  10. Connexins and Glucose Metabolism in Cancer.
  11. Metabolic regulation and function of T helper cells in neuroinflammation.
  12. Relationship between metabolic reprogramming and drug resistance in breast cancer.
  13. MYCN and Metabolic Reprogramming in Neuroblastoma.
  14. An exercise-induced metabolic shield in distant organs blocks cancer progression and metastatic dissemination.
  15. Cancer Metabolism and Ischemia-Reperfusion Injury: Two Sides of the Same Coin.
  16. Revisited Metabolic Control and Reprogramming Cancers by Means of the Warburg Effect in Tumor Cells.
  17. The role of metabolic reprogramming in cancer metastasis and potential mechanism of traditional Chinese medicine intervention.
  18. Diet and Exercise in Cancer Metabolism.
  19. The amino acid transporter SLC7A11-mediated crosstalk implicated in cancer therapy and the tumor microenvironment.
  20. Intestinal Klebsiella pneumoniae Contributes to Pneumonia by Synthesizing Glutamine in Multiple Myeloma.
  1. Cancer Res Commun. 2022 Aug;2(8): 784-794
    GLS1 is a protective factor in patients with ovarian clear cell carcinoma and its expression does not correlate with ARID1A-mutated tumors.
    Valentino Clemente, Asumi Hoshino, Mihir Shetty, Andrew Nelson, Britt K Erickson, Ruth Baker, Nathan Rubin, Mahmoud Khalifa, S John Weroha, Emil Lou, Martina Bazzaro.
      Targeting glutamine metabolism has emerged as a novel therapeutic strategy for several human cancers, including ovarian cancer. The primary target of this approach is the kidney isoform of glutaminase, glutaminase 1 (GLS1), a key enzyme in glutamine metabolism that is overexpressed in several human cancers. A first-in-class inhibitor of GLS1, called CB839 (Telaglenastat), has been investigated in several clinical trials, with promising results. The first clinical trial of CB839 in platinum-resistant ovarian cancer patients is forthcoming. ARID1A-mutated ovarian clear cell carcinoma (OCCC) is a relatively indolent and chemoresistant ovarian cancer histotype. In OCCC-derived cells ARID1A simultaneously drives GLS1 expression and metabolism reprograming. In ARID1A-mutated OCCC-derived mouse models, loss of ARID1A corresponds to GLS1 upregulation and increases sensitivity to GLS1 inhibition. Thus, targeting of GLS1 with CB839 has been suggested as a targeted approach for OCCC patients with tumors harboring ARID1A-mutations. Here, we investigated whether GLS1 is differentially expressed between OCCC patients whose tumors are ARID1A positive and patients whose tumors are ARID1A negative. In clinical specimens of OCCC, we found that GLS1 overexpression was not correlated with ARID1A loss. In addition, GLS1 overexpression was associated with better clinical outcomes. Our findings have implications for human trials using experimental therapeutics targeting GLS1.
    Keywords:  ARID1A; CB839; GLS1; Glutaminase; Glutaminase inhibitor; Glutamine; OCCC
    DOI:  https://doi.org/10.1158/2767-9764.crc-22-0122
  2. Int J Mol Sci. 2022 Sep 03. pii: 10086. [Epub ahead of print]23(17):
    Hormone-Glutamine Metabolism: A Critical Regulatory Axis in Endocrine-Related Cancers.
    Fengyuan Xu, Jialu Shi, Xueyun Qin, Zimeng Zheng, Min Chen, Zhi Lin, Jiangfeng Ye, Mingqing Li.
      The endocrine-related cancers and hormones are undoubtedly highly interconnected. How hormones support or repress tumor induction and progression has been extensively profiled. Furthermore, advances in understanding the role of glutamine metabolism in mediating tumorigenesis and development, coupled with these in-depth studies on hormone (e.g., estrogen, progesterone, androgen, prostaglandin, thyroid hormone, and insulin) regulation of glutamine metabolism, have led us to think about the relationship between these three factors, which remains to be elucidated. Accordingly, in this review, we present an updated overview of glutamine metabolism traits and its influence on endocrine oncology, as well as its upstream hormonal regulation. More importantly, this hormone/glutamine metabolism axis may help in the discovery of novel therapeutic strategies for endocrine-related cancer.
    Keywords:  androgen; estrogen; glutamine; hormone; insulin; progesterone; prostaglandin; thyroid hormone
    DOI:  https://doi.org/10.3390/ijms231710086
  3. Front Oncol. 2022 ;12 968351
    Metabolic management of microenvironment acidity in glioblastoma.
    Thomas N Seyfried, Gabriel Arismendi-Morillo, Giulio Zuccoli, Derek C Lee, Tomas Duraj, Ahmed M Elsakka, Joseph C Maroon, Purna Mukherjee, Linh Ta, Laura Shelton, Dominic D'Agostino, Michael Kiebish, Christos Chinopoulos.
      Glioblastoma (GBM), similar to most cancers, is dependent on fermentation metabolism for the synthesis of biomass and energy (ATP) regardless of the cellular or genetic heterogeneity seen within the tumor. The transition from respiration to fermentation arises from the documented defects in the number, the structure, and the function of mitochondria and mitochondrial-associated membranes in GBM tissue. Glucose and glutamine are the major fermentable fuels that drive GBM growth. The major waste products of GBM cell fermentation (lactic acid, glutamic acid, and succinic acid) will acidify the microenvironment and are largely responsible for drug resistance, enhanced invasion, immunosuppression, and metastasis. Besides surgical debulking, therapies used for GBM management (radiation, chemotherapy, and steroids) enhance microenvironment acidification and, although often providing a time-limited disease control, will thus favor tumor recurrence and complications. The simultaneous restriction of glucose and glutamine, while elevating non-fermentable, anti-inflammatory ketone bodies, can help restore the pH balance of the microenvironment while, at the same time, providing a non-toxic therapeutic strategy for killing most of the neoplastic cells.
    Keywords:  fermentation; glutamate; glutaminolysis; glycolysis; ketogenic diet; ketogenic metabolic therapy; lactate; succinate
    DOI:  https://doi.org/10.3389/fonc.2022.968351
  4. Front Pharmacol. 2022 ;13 950886
    The roles of glycolysis in osteosarcoma.
    Zuxi Feng, Yanghuan Ou, Liang Hao.
      Metabolic reprogramming is of great significance in the progression of various cancers and is critical for cancer progression, diagnosis, and treatment. Cellular metabolic pathways mainly include glycolysis, fat metabolism, glutamine decomposition, and oxidative phosphorylation. In cancer cells, reprogramming metabolic pathways is used to meet the massive energy requirement for tumorigenesis and development. Metabolisms are also altered in malignant osteosarcoma (OS) cells. Among reprogrammed metabolisms, alterations in aerobic glycolysis are key to the massive biosynthesis and energy demands of OS cells to sustain their growth and metastasis. Numerous studies have demonstrated that compared to normal cells, glycolysis in OS cells under aerobic conditions is substantially enhanced to promote malignant behaviors such as proliferation, invasion, metastasis, and drug resistance of OS. Glycolysis in OS is closely related to various oncogenes and tumor suppressor genes, and numerous signaling pathways have been reported to be involved in the regulation of glycolysis. In recent years, a vast number of inhibitors and natural products have been discovered to inhibit OS progression by targeting glycolysis-related proteins. These potential inhibitors and natural products may be ideal candidates for the treatment of osteosarcoma following hundreds of preclinical and clinical trials. In this article, we explore key pathways, glycolysis enzymes, non-coding RNAs, inhibitors, and natural products regulating aerobic glycolysis in OS cells to gain a deeper understanding of the relationship between glycolysis and the progression of OS and discover novel therapeutic approaches targeting glycolytic metabolism in OS.
    Keywords:  Cancer Progression; glycolysis; key enzymes; osteosarcoma; signaling pathway
    DOI:  https://doi.org/10.3389/fphar.2022.950886
  5. Anticancer Agents Med Chem. 2022 Sep 05.
    Targeting Glutaminolysis to treat Multiple Myeloma: An In Vitro Evaluation of Glutaminase Inhibitors Telaglenastat and Epigallocatechin-3-gallate.
    Chen Li, Yuhu Feng, Weiguo Wang, Lingyun Xu, Miao Zhang, Yue Yao, Xiaoqian Wu, Qin Zhang, Wenyue Huang, Xiuxiu Wang, Xue Li, Peipei Ying, Liu Shang.
       BACKGROUND: Cancer is associated with metabolic changes from increased cell proliferation and growth. Compared to normal differentiated cells, MM cells use the glycolytic pathway even when adequate oxygen is present triggering "Glutamine addiction."
    OBJECTIVE: To investigate the single and combined effects of epigallocatechin-3-gallate (EGCG) and telaglenastat, a glutaminase inhibitor, on the proliferation and apoptosis of the multiple myeloma cell line KM3/BTZ.
    METHODS: KM3/BTZ cells were treated with different concentrations of telaglenastat and EGCG alone or in combination to investigate their effect on proliferation and apoptosis using the CCK8 assay, flow cytometry, and western blotting. The Chou-Talalay combination index analysis was used to explore the effect of telaglenastat combined with EGCG, while the Combination Index (CI) was calculated to analyze whether the combination of the two drugs had a synergistic effect.
    RESULTS: Telaglenastat and EGCG alone as well as in combination (5 µmol/L telaglenastat + 120 µmol/L EGCG) significantly inhibited the proliferation of KM3/BTZ cells compared to the inhibition effect of the control. Additionally, the combined treatment increased the proportion of KM3/BTZ cells in the G2 phase and decreased the proportion of cells in the G1 phase. The apoptosis rate of EGCG alone and the combined treatment was significantly higher than that of the control group. Bax protein expression was highest in the combined treatment group, whereas Bcl-2 expression was lowest, with the combined treatment group having the highest ratio of Bax/Bcl-2.
    CONCLUSION: Telaglenastat and EGCG act synergistically to inhibit cell proliferation and promote apoptosis in KM3/BTZ cells, possibly by targeting glutamine metabolism and glycolysis.
    Keywords:  EGCG; KM3/BTZ cell; Telaglenastat; cell apoptosis; cell proliferation
    DOI:  https://doi.org/10.2174/1871520622666220905142338
  6. Talanta. 2022 Sep 02. pii: S0039-9140(22)00695-6. [Epub ahead of print]253 123899
    An optimized method for estimating glutaminase activity in biological samples.
    Lamia A Almashhedy, Mahmoud Hussein Hadwan, Dunia Abbas Khudhair, Mohammed A Kadhum, Asad M Hadwan, Muntadhar M Hadwan.
      Spectrophotometric methodologies have been used to assess glutaminase activity, for which coloured complexes have been developed that measure spectrophotometry across the visible spectrum using different reagents. The present paper describes a precise, simple and reliable procedure for quantifying glutaminase activity, which is a key enzyme in glutamine hydrolysis and also involved in glutamine metabolism regulation. The procedure presented here measures glutaminase activity by incubating glutaminase enzyme at 37 °C for 20 min with a glutamine substrate dissolved in a buffer (pH 8.6). The enzymatic reaction contains suitable activity of glutamate oxidase, which acts to convert glutamate to hydrogen peroxide and 2-oxoglutarate. To terminate the enzymatic activity, a working solution containing pyridine-2,6-dicarboxylic (PDA) acid and ammonium vanadate (AV) was added following incubation. Oxo-peroxo-pyridine-2,6-dicarboxylato-vanadate (OPDV), a stable orange-coloured chelate complex measuring 435 nm spectrophotometrically, was produced by the interaction between the generated hydrogen peroxide and the supplied reagent. Using the response surface methodology (RSM) as an indicator of the assay's accuracy, we employed the Box-Behnken design (BBD) to improve the method's design (the OPDV-Glutaminase assay). Improvement factors were the volume of working reagent solution (PDA/AV), volume of glutamate oxidase solution (GO), and incubation time. In matched samples, this novel method was verified against a Bland-Altman plot assessment of glutaminase activity using the indophenol methodology. A correlation value of 0.99 between the two methods' comparisons showed that the novel protocol was equally applicable to the reference method.
    Keywords:  Box-behnken design; Enzyme assessment; Glutaminase activity; Response surface methodology; Spectrophotometry
    DOI:  https://doi.org/10.1016/j.talanta.2022.123899
  7. Cell Mol Life Sci. 2022 Sep 04. 79(9): 505
    Small leucine zipper protein functions as a modulator for metabolic reprogramming of colorectal cancer cells by inducing nutrient stress-mediated autophagy.
    Suhyun Kim, Minseok Oh, Minsoo Kang, Jesang Ko.
      In multiple cancers, autophagy promotes tumor development by recycling intracellular components into metabolic pathways. Autophagy-induced metabolic reprogramming and plasticity lead to cancer cell survival and resistance to anticancer therapy. We investigated the role of small leucine zipper protein (sLZIP) in autophagy and cell survival under nutrient-deficient conditions in colorectal cancer (CRC). sLZIP was induced by nutrient stress and increased the transcription of microtubule-associated protein 1A/1B-light chain 3 (LC3), by directly binding to its promoter. Under nutrient stress conditions, sLZIP activated autophagy and promoted the survival of CRC cells. sLZIP induced metabolic reprogramming of CRC cells, to activate glutaminolysis and the tricarboxylic acid cycle. sLZIP also enhanced the autophagic degradation of Keap1 and the nuclear accumulation of Nrf2, leading to NQO1 expression, for maintenance of redox homeostasis. sLZIP-knockout CRC cells exhibited impaired autophagy induction in the glycolytic inhibition state. Xenograft mice lacking sLZIP showed decreased tumor growth, by rendering CRC cells sensitive to glycolysis inhibition. The expression of sLZIP and LC3B was highly elevated in tumors of CRC patients compared to that in normal tissues, and correlated with the progression of CRC. These findings suggest that sLZIP drives autophagy and metabolic reprogramming to promote colorectal tumorigenesis.
    Keywords:  Autophagy; Colorectal cancer; Metabolic reprogramming; Transcriptional regulation
    DOI:  https://doi.org/10.1007/s00018-022-04535-4
  8. Front Immunol. 2022 ;13 897862
    Multiple myeloma metabolism - a treasure trove of therapeutic targets?
    Monica Roman-Trufero, Holger W Auner, Claire M Edwards.
      Multiple myeloma is an incurable cancer of plasma cells that is predominantly located in the bone marrow. Multiple myeloma cells are characterized by distinctive biological features that are intricately linked to their core function, the assembly and secretion of large amounts of antibodies, and their diverse interactions with the bone marrow microenvironment. Here, we provide a concise and introductory discussion of major metabolic hallmarks of plasma cells and myeloma cells, their roles in myeloma development and progression, and how they could be exploited for therapeutic purposes. We review the role of glucose consumption and catabolism, assess the dependency on glutamine to support key metabolic processes, and consider metabolic adaptations in drug-resistant myeloma cells. Finally, we examine the complex metabolic effects of proteasome inhibitors on myeloma cells and the extracellular matrix, and we explore the complex relationship between myeloma cells and bone marrow adipocytes.
    Keywords:  bone marrow (BM) adipocytes; cancer biology; metabolism; multiple myeloma; plasma cell; proteasome; proteostasis
    DOI:  https://doi.org/10.3389/fimmu.2022.897862
  9. IUBMB Life. 2022 Sep 09.
    Structural aspects of the glucose and monocarboxylate transporters involved in the Warburg effect.
    Xin Jiang, Nieng Yan, Dong Deng, Chuangye Yan.
      Cancer cells shift their glucose catabolism from aerobic respiration to lactic fermentation even in the presence of oxygen, and this is known as the "Warburg effect". To accommodate the high glucose demands and to avoid lactate accumulation, the expression levels of human glucose transporters (GLUTs) and human monocarboxylate transporters (MCTs) are elevated to maintain metabolic homeostasis. Therefore, inhibition of GLUTs and/or MCTs provides potential therapeutic strategies for cancer treatment. Here, we summarize recent advances in the structural characterization of GLUTs and MCTs, providing a comprehensive understanding of their transport and inhibition mechanisms to facilitate further development of anticancer therapies.
    Keywords:  Warburg effect; alternating access; glucose transporters; lactate shuttling; monocarboxylate transporters
    DOI:  https://doi.org/10.1002/iub.2668
  10. Int J Mol Sci. 2022 Sep 05. pii: 10172. [Epub ahead of print]23(17):
    Connexins and Glucose Metabolism in Cancer.
    Jennifer C Jones, Thomas M Bodenstine.
      Connexins are a family of transmembrane proteins that regulate diverse cellular functions. Originally characterized for their ability to mediate direct intercellular communication through the formation of highly regulated membrane channels, their functions have been extended to the exchange of molecules with the extracellular environment, and the ability to modulate numerous channel-independent effects on processes such as motility and survival. Notably, connexins have been implicated in cancer biology for their context-dependent roles that can both promote or suppress cancer cell function. Moreover, connexins are able to mediate many aspects of cellular metabolism including the intercellular coupling of nutrients and signaling molecules. During cancer progression, changes to substrate utilization occur to support energy production and biomass accumulation. This results in metabolic plasticity that promotes cell survival and proliferation, and can impact therapeutic resistance. Significant progress has been made in our understanding of connexin and cancer biology, however, delineating the roles these multi-faceted proteins play in metabolic adaptation of cancer cells is just beginning. Glucose represents a major carbon substrate for energy production, nucleotide synthesis, carbohydrate modifications and generation of biosynthetic intermediates. While cancer cells often exhibit a dependence on glycolytic metabolism for survival, cellular reprogramming of metabolic pathways is common when blood perfusion is limited in growing tumors. These metabolic changes drive aggressive phenotypes through the acquisition of functional traits. Connections between glucose metabolism and connexin function in cancer cells and the surrounding stroma are now apparent, however much remains to be discovered regarding these relationships. This review discusses the existing evidence in this area and highlights directions for continued investigation.
    Keywords:  connexin; gap junction; glucose; metabolism
    DOI:  https://doi.org/10.3390/ijms231710172
  11. Semin Immunopathol. 2022 Sep 06.
    Metabolic regulation and function of T helper cells in neuroinflammation.
    Martina Spiljar, Vijay K Kuchroo.
      Neuroinflammatory conditions such as multiple sclerosis (MS) are initiated by pathogenic immune cells invading the central nervous system (CNS). Autoreactive CD4+ T helper cells are critical players that orchestrate the immune response both in MS and in other neuroinflammatory autoimmune diseases including animal models that have been developed for MS. T helper cells are classically categorized into different subsets, but heterogeneity exists within these subsets. Untangling the more complex regulation of these subsets will clarify their functional roles in neuroinflammation. Here, we will discuss how differentiation, immune checkpoint pathways, transcriptional regulation and metabolic factors determine the function of CD4+ T cell subsets in CNS autoimmunity. T cells rely on metabolic reprogramming for their activation and proliferation to meet bioenergetic demands. This includes changes in glycolysis, glutamine metabolism and polyamine metabolism. Importantly, these pathways were recently also implicated in the fine tuning of T cell fate decisions during neuroinflammation. A particular focus of this review will be on the Th17/Treg balance and intra-subset functional states that can either promote or dampen autoimmune responses in the CNS and thus affect disease outcome. An increased understanding of factors that could tip CD4+ T cell subsets and populations towards an anti-inflammatory phenotype will be critical to better understand neuroinflammatory diseases and pave the way for novel treatment paradigms.
    Keywords:  Experimental autoimmune encephalomyelitis; Immunometabolism; Multiple sclerosis; Neuroimmunology; Neuroinflammation; Th17 cells
    DOI:  https://doi.org/10.1007/s00281-022-00959-z
  12. Front Oncol. 2022 ;12 942064
    Relationship between metabolic reprogramming and drug resistance in breast cancer.
    Linlin Lv, Shilei Yang, Yanna Zhu, Xiaohan Zhai, Shuai Li, Xufeng Tao, Deshi Dong.
      Breast cancer is the leading cause of cancer death in women. At present, chemotherapy is the main method to treat breast cancer in addition to surgery and radiotherapy, but the process of chemotherapy is often accompanied by the development of drug resistance, which leads to a reduction in drug efficacy. Furthermore, mounting evidence indicates that drug resistance is caused by dysregulated cellular metabolism, and metabolic reprogramming, including enhanced glucose metabolism, fatty acid synthesis and glutamine metabolic rates, is one of the hallmarks of cancer. Changes in metabolism have been considered one of the most important causes of resistance to treatment, and knowledge of the mechanisms involved will help in identifying potential treatment deficiencies. To improve women's survival outcomes, it is vital to elucidate the relationship between metabolic reprogramming and drug resistance in breast cancer. This review analyzes and investigates the reprogramming of metabolism and resistance to breast cancer therapy, and the results offer promise for novel targeted and cell-based therapies.
    Keywords:  Breast cancer; drug resistance; fatty acid synthesis; glucose metabolism; metabolic reprogramming
    DOI:  https://doi.org/10.3389/fonc.2022.942064
  13. Cancers (Basel). 2022 Aug 25. pii: 4113. [Epub ahead of print]14(17):
    MYCN and Metabolic Reprogramming in Neuroblastoma.
    Mohit Bansal, Anamika Gupta, Han-Fei Ding.
      Neuroblastoma is a pediatric cancer responsible for approximately 15% of all childhood cancer deaths. Aberrant MYCN activation, as a result of genomic MYCN amplification, is a major driver of high-risk neuroblastoma, which has an overall survival rate of less than 50%, despite the best treatments currently available. Metabolic reprogramming is an integral part of the growth-promoting program driven by MYCN, which fuels cell growth and proliferation by increasing the uptake and catabolism of nutrients, biosynthesis of macromolecules, and production of energy. This reprogramming process also generates metabolic vulnerabilities that can be exploited for therapy. In this review, we present our current understanding of metabolic reprogramming in neuroblastoma, focusing on transcriptional regulation as a key mechanism in driving the reprogramming process. We also highlight some important areas that need to be explored for the successful development of metabolism-based therapy against high-risk neuroblastoma.
    Keywords:  MYCN; cancer metabolism; metabolic reprogramming; neuroblastoma; pediatric cancer
    DOI:  https://doi.org/10.3390/cancers14174113
  14. Cancer Res. 2022 Sep 09. pii: CAN-22-0237. [Epub ahead of print]
    An exercise-induced metabolic shield in distant organs blocks cancer progression and metastatic dissemination.
    Danna Sheinboim, Shivang Parikh, Paulee Manich, Irit Markus, Sapir Dahan, Roma Parikh, Elisa Stubbs, Gali Cohen, Valentina Zemser-Werner, Rachel E Bell, Sara Arciniegas Ruiz, Ruth Percik, Ronen Brenner, Stav Leibou, Hananya Vaknine, Gali Arad, Yariv Gerber, Lital Keinan Boker, Tal Shimony, Lior Bikovski, Nir Goldstein, Keren Constantini, Sapir Labes, Shimonov Mordechai, Hila Doron, Ariel Ionescu, Tamar Ziv, Eran Nizri, Guy Choshen, Hagit Eldar-Finkelman, Yuval Tabach, Aharon Helman, Shamgar Ben-Eliyahu, Neta Erez, Eran Perlson, Tamar Geiger, Danny Ben-Zvi, Mehdi Khaled, Yftach Gepner, Carmit Levy.
      Exercise prevents cancer incidence and recurrence, yet the underlying mechanism behind this relationship remains mostly unknown. Here we report that exercise induces metabolic reprogramming of internal organs that increases nutrient demand and protects against metastatic colonization by limiting nutrient availability to the tumor, generating an exercise-induced metabolic shield. Proteomic and ex vivo metabolic capacity analyses of murine internal organs revealed that exercise induces catabolic processes, glucose uptake, mitochondrial activity, and GLUT expression. Proteomic analysis of routinely active human subject plasma demonstrated increased carbohydrate utilization following exercise. Epidemiological data from a 20-year prospective study of a large human cohort of initially cancer-free participants revealed that exercise prior to cancer initiation had a modest impact on cancer incidence in low metastatic stages but significantly reduced the likelihood of highly metastatic cancer. In three models of melanoma in mice, exercise prior to cancer injection significantly protected against metastases in distant organs. The protective effects of exercise were dependent on mTOR activity, and inhibition of the mTOR pathway with rapamycin treatment ex vivo reversed the exercise-induced metabolic shield. Under limited glucose conditions, active stroma consumed significantly more glucose at the expense of the tumor. Collectively, these data suggest a clash between the metabolic plasticity of cancer and exercise-induced metabolic reprogramming of the stroma, raising an opportunity to block metastasis by challenging the metabolic needs of the tumor.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-0237
  15. J Clin Med. 2022 Aug 30. pii: 5096. [Epub ahead of print]11(17):
    Cancer Metabolism and Ischemia-Reperfusion Injury: Two Sides of the Same Coin.
    Denise V Nemeth, Enke Baldini, Salvatore Sorrenti, Vito D'Andrea, Maria Irene Bellini.
      Cancer cells are characterized by the reprogramming of certain cell metabolisms via activation of definite pathways and regulation of gene signaling. Ischemia-reperfusion injury (IRI) is characterized by tissue damage and death following a lack of perfusion and oxygenation. It is most commonly seen in the setting of organ transplantation. Interestingly, the microenvironments seen in cancer and ischemic tissues are quite similar, especially due to the hypoxic state that occurs in both. As a consequence, there is genetic signaling involved in response to IRI that has common pathways with cancer. Some of these changes are seen across the board with many cancer cells and are known as Hallmarks of Cancer, among which are aerobic glycolysis and the induction of angiogenesis. This literature review aims to compare the metabolic pathways that are altered in cancer tissues and in normal tissues subjected to IRI in order to find common adaptive processes and to identify key pathways that could represent a therapeutic target in both pathologies. By increasing our understanding of this relationship, clinical correlations can be made and applied practically to improve outcomes of transplanted organs, given the known association with acute rejection, delayed graft function, and poor graft survival. The following metabolic pathways are discussed in our review, both in the setting of cancer and IRI: apoptosis, glycolysis, and angiogenesis. The role of the immune system in both pathologies as well as mitochondrial function and the production of reactive oxygen species (ROS) are reviewed.
    Keywords:  aerobic glycolysis; angiogenesis; apoptosis; cancer cell metabolism; hallmarks of cancer; ischemia-reperfusion injury; tumorigenesis
    DOI:  https://doi.org/10.3390/jcm11175096
  16. Int J Mol Sci. 2022 Sep 02. pii: 10037. [Epub ahead of print]23(17):
    Revisited Metabolic Control and Reprogramming Cancers by Means of the Warburg Effect in Tumor Cells.
    Abekura Fukushi, Hee-Do Kim, Yu-Chan Chang, Cheorl-Ho Kim.
      Aerobic glycolysis is an emerging hallmark of many human cancers, as cancer cells are defined as a "metabolically abnormal system". Carbohydrates are metabolically reprogrammed by its metabolizing and catabolizing enzymes in such abnormal cancer cells. Normal cells acquire their energy from oxidative phosphorylation, while cancer cells acquire their energy from oxidative glycolysis, known as the "Warburg effect". Energy-metabolic differences are easily found in the growth, invasion, immune escape and anti-tumor drug resistance of cancer cells. The glycolysis pathway is carried out in multiple enzymatic steps and yields two pyruvate molecules from one glucose (Glc) molecule by orchestral reaction of enzymes. Uncontrolled glycolysis or abnormally activated glycolysis is easily observed in the metabolism of cancer cells with enhanced levels of glycolytic proteins and enzymatic activities. In the "Warburg effect", tumor cells utilize energy supplied from lactic acid-based fermentative glycolysis operated by glycolysis-specific enzymes of hexokinase (HK), keto-HK-A, Glc-6-phosphate isomerase, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase, phosphofructokinase (PFK), phosphor-Glc isomerase (PGI), fructose-bisphosphate aldolase, phosphoglycerate (PG) kinase (PGK)1, triose phosphate isomerase, PG mutase (PGAM), glyceraldehyde-3-phosphate dehydrogenase, enolase, pyruvate kinase isozyme type M2 (PKM2), pyruvate dehydrogenase (PDH), PDH kinase and lactate dehydrogenase. They are related to glycolytic flux. The key enzymes involved in glycolysis are directly linked to oncogenesis and drug resistance. Among the metabolic enzymes, PKM2, PGK1, HK, keto-HK-A and nucleoside diphosphate kinase also have protein kinase activities. Because glycolysis-generated energy is not enough, the cancer cell-favored glycolysis to produce low ATP level seems to be non-efficient for cancer growth and self-protection. Thus, the Warburg effect is still an attractive phenomenon to understand the metabolic glycolysis favored in cancer. If the basic properties of the Warburg effect, including genetic mutations and signaling shifts are considered, anti-cancer therapeutic targets can be raised. Specific therapeutics targeting metabolic enzymes in aerobic glycolysis and hypoxic microenvironments have been developed to kill tumor cells. The present review deals with the tumor-specific Warburg effect with the revisited viewpoint of recent progress.
    Keywords:  Metabolic enzyme; Warburg’s effect; aerobic glycolysis; apoptotic death; carbohydrate metabolic reprogramming; cytosolic to mitochondrial pathway determinant; glucose utilization; metabolic selectivity
    DOI:  https://doi.org/10.3390/ijms231710037
  17. Biomed Pharmacother. 2022 Sep;pii: S0753-3322(22)00765-X. [Epub ahead of print]153 113376
    The role of metabolic reprogramming in cancer metastasis and potential mechanism of traditional Chinese medicine intervention.
    Dong Wang, Fangyuan Wang, Xianbin Kong, Qingbo Li, Haoyang Shi, Shuang Zhao, Wen Li, Yu Li, Jingyan Meng.
      Metabolic reprogramming is one of the most prominent features underlying cancer cells progression and metastasis.Traditional Chinese medicine (TCM) has been widely used in the clinical treatment of cancer, with the advantages of multi-pathway, multi-target, multi-component anti-tumor pharmacological effects and low risk of adverse effects. However, the mechanisms underlying the anti-tumor effects of TCM are not fully understood, especially on cellular metabolic reprogramming. In this review, we summarize the role of glucose, lipid and amino acid metabolism in cancer metastasis, which is key in cancer cells and tumor micro-environment (TME) cell metabolism. Furthermore, we reviewed the potential mechanisms by which, most bioactive TCM compounds suppress cancer metastasis by regulating metabolic reprogramming and the possibility of sensitizing other anti-tumor drugs. TCM and its bioactive compounds have huge prospects for clinical application in the treatment of cancer metastasis. Unfortunately, little is currently known about the regulatory effects of Chinese herbal medicines and their bioactive compounds on the metabolic reprogramming of cancer cells and the combination therapy for cancers. This review provides novel insights into the regulation of metabolic reprogramming by TCM in combination with other anti-tumor drugs against cancer metastasis and the possibility of becoming sensitizers for other anti-tumor drugs.
    Keywords:  Cancer metastasis; Metabolic reprogramming; TME cells; Traditional Chinese medicine; Tumor micro-environment
    DOI:  https://doi.org/10.1016/j.biopha.2022.113376
  18. Cancer Discov. 2022 Sep 05. OF1-OF9
    Diet and Exercise in Cancer Metabolism.
    Jason W Locasale.
      Diet and exercise are modifiable lifestyle factors known to have a major influence on metabolism. Clinical practice addresses diseases of altered metabolism such as diabetes or hypertension by altering these factors. Despite enormous public interest, there are limited defined diet and exercise regimens for patients with cancer. Nevertheless, the molecular basis of cancer has converged over the past 15 years on an essential role for altered metabolism in cancer. However, our understanding of the molecular mechanisms that underlie the impact of diet and exercise on cancer metabolism is in its very early stages. In this perspective, I propose conceptual frameworks for understanding the consequences of diet and exercise on cancer cell metabolism and tumor biology and also highlight recent developments. By advancing our mechanistic understanding, I will discuss actionable ways that such interventions could eventually reach the mainstay of both medical oncology and cancer control and prevention.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-0096
  19. Biochem Pharmacol. 2022 Sep 06. pii: S0006-2952(22)00335-5. [Epub ahead of print] 115241
    The amino acid transporter SLC7A11-mediated crosstalk implicated in cancer therapy and the tumor microenvironment.
    Jiaqin He, Xiaomeng Wang, Keying Chen, Mei Zhang, Juan Wang.
      The solute carrier family 7 member 11 (SLC7A11), an amino acid transporter protein is frequently overexpressed in human malignancies. The expression and activity of SLC7A11 is finely regulated by oncogenes and tumor suppressors in tumor cells through various mechanisms and is highly specific for cystine and glutamate. Cystine is mainly transported intracellularly by SLC7A11 in the tumor microenvironment (TME) and is involved in GSH synthesis, which leads to ferroptosis resistance in tumor cells and promotes tumorigenesis and progression. The downregulation of SLC7A11 presents a unique drug discovery opportunity for ferroptosis-related diseases. Experimental work has shown that targeting SLC7A11 and tumor immunotherapy combine to trigger ferroptosis more potently. Moreover, immunotargeting of SLC7A11 increases the chemosensitivity of cancer stem cells to doxorubicin, suggesting that it may act as an adjuvant to chemotherapy. Thus, SLC7A11 could be a promising target to overcome resistance mechanisms in conventional cancer treatments. This review provides an overview of the regulatory network of SLC7A11 in the TME and progress in the development of SLC7A11 inhibitors. In addition, we summarize the cytotoxic effects of blocking SLC7A11 in cancer cells, cancer stem cells and immune cells.
    Keywords:  Anticancer; Ferroptosis; Immunotherapy; SLC7A11; SLC7A11 inhibitors
    DOI:  https://doi.org/10.1016/j.bcp.2022.115241
  20. Cancers (Basel). 2022 Aug 29. pii: 4188. [Epub ahead of print]14(17):
    Intestinal Klebsiella pneumoniae Contributes to Pneumonia by Synthesizing Glutamine in Multiple Myeloma.
    Yihui Wang, Qin Yang, Yinghong Zhu, Xingxing Jian, Jiaojiao Guo, Jingyu Zhang, Chunmei Kuang, Xiangling Feng, Gang An, Lugui Qiu, Guancheng Li, Yanjuan He, Wen Zhou.
      Pneumonia accounts for a significant cause of morbidity and mortality in multiple myeloma (MM) patients. It has been previously shown that intestinal Klebsiella pneumonia (K. pneumonia) enriches in MM and promotes MM progression. However, what role the altered gut microbiota plays in MM with pneumonia remains unknown. Here, we show that intestinal K. pneumonia is significantly enriched in MM with pneumonia. This enriched intestinal K. pneumonia links to the incidence of pneumonia in MM, and intestinal colonization of K. pneumonia contributes to pneumonia in a 5TGM1 MM mice model. Further targeted metabolomic assays reveal the elevated level of glutamine, which is consistently increased with the enrichment of K. pneumonia in MM mice and patients, is synthesized by K. pneumonia, and leads to the elevated secretion of TNF-α in the lung normal fibroblast cells for the higher incidence of pneumonia. Inhibiting glutamine synthesis by establishing glnA-mutated K. pneumonia alleviates the incidence of pneumonia in the 5TGM1 MM mice model. Overall, our work proposes that intestinal K. pneumonia indirectly contributes to pneumonia in MM by synthesizing glutamine. Altogether, we unveil a gut-lung axis in MM with pneumonia and establish a novel mechanism and a possible intervention strategy for MM with pneumonia.
    Keywords:  Klebsiella pneumonia; glutamine; gut microbiome; multiple myeloma; pneumonia
    DOI:  https://doi.org/10.3390/cancers14174188
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