bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2021–01–03
twenty-two papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. The Metabolic Importance of the Glutaminase II Pathway in Normal and Cancerous Cells.
  2. Coenzyme Q Depletion Reshapes MCF-7 Cells Metabolism.
  3. High Fructose Drives the Serine Synthesis Pathway in Acute Myeloid Leukemic Cells.
  4. Reductive TCA cycle metabolism fuels glutamine- and glucose-stimulated insulin secretion.
  5. Non-canonical Glutamate-Cysteine Ligase Activity Protects against Ferroptosis.
  6. Non-Invasive Human Embryo Metabolic Assessment as a Developmental Criterion.
  7. Glutamine pretreatment protects bovine mammary epithelial cells from inflammation and oxidative stress induced by γ-d-glutamyl-meso-diaminopimelic acid (iE-DAP).
  8. Ascorbate kills breast cancer cells by rewiring metabolism via redox imbalance and energy crisis.
  9. Amino Acid Transporters Are a Vital Focal Point in the Control of mTORC1 Signaling and Cancer.
  10. Regulation of Autophagy by Glycolysis in Cancer.
  11. Metabolomic Analysis to Elucidate Mechanisms of Sunitinib Resistance in Renal Cell Carcinoma.
  12. Illuminating the cross-talk between tumor metabolism and immunity in IDH-mutated cancers.
  13. Prostate cancer C5a receptor expression and augmentation of cancer cell proliferation, invasion, and PD-L1 expression by C5a.
  14. Interplay among Oxidative Stress, Methylglyoxal Pathway and S-Glutathionylation.
  15. The glutaminase inhibitor CB-839 (Telaglenastat) enhances the anti-melanoma activity of T cell mediated immunotherapies.
  16. Effects of cellular senescence on metabolic pathways in non-immune and immune cells.
  17. Abrogating GPT2 in triple negative breast cancer inhibits tumor growth and promotes autophagy.
  18. Proteins moonlighting in tumor metabolism and epigenetics.
  19. Glutamine metabolite α-ketoglutarate acts as an epigenetic co-factor to interfere with osteoclast differentiation.
  20. Exploration the Mechanism of Doxorubicin-Induced Heart Failure in Rats by Integration of Proteomics and Metabolomics Data.
  21. Critical role of mTOR in regulating aerobic glycolysis in carcinogenesis (Review).
  22. How Autophagy Shapes the Tumor Microenvironment in Ovarian Cancer.
  1. Anal Biochem. 2020 Dec 19. pii: S0003-2697(20)30615-1. [Epub ahead of print] 114083
    The Metabolic Importance of the Glutaminase II Pathway in Normal and Cancerous Cells.
    Thambi Dorai, John T Pinto, Travis T Denton, Boris F Krasnikov, Arthur J L Cooper.
      In rapidly dividing cells, including many cancer cells, l-glutamine is a major energy source. Utilization of glutamine is usually depicted as: l-glutamine → l-glutamate (catalyzed by glutaminase isozymes; GLS1 and GLS2), followed by l-glutamate → α-ketoglutarate [catalyzed by glutamate-linked aminotransferases or by glutamate dehydrogenase (GDH)]. α-Ketoglutarate is a major anaplerotic component of the tricarboxylic acid (TCA) cycle. However, the glutaminase II pathway also converts l-glutamine to α-ketoglutarate. This pathway consists of a glutamine transaminase coupled to ω-amidase [Net reaction: L-Glutamine + α-keto acid + H2O → α-ketoglutarate + L-amino acid + NH4+]. This review focuses on the biological importance of the glutaminase II pathway, especially in relation to metabolism of cancer cells. Our studies suggest a component enzyme of the glutaminase II pathway, ω-amidase, is utilized by tumor cells to provide anaplerotic carbon. Inhibitors of GLS1 are currently in clinical trials as anti-cancer agents. However, this treatment will not prevent the glutaminase II pathway from providing anaplerotic carbon derived from glutamine. Specific inhibitors of ω-amidase, perhaps in combination with a GLS1 inhibitor, may provide greater therapeutic efficacy.
    Keywords:  Glutaminase II pathway; Glutamine addiction in cancer; Glutamine transaminases; α-Ketoglutaramate; ω-Amidase
    DOI:  https://doi.org/10.1016/j.ab.2020.114083
  2. Int J Mol Sci. 2020 Dec 28. pii: E198. [Epub ahead of print]22(1):
    Coenzyme Q Depletion Reshapes MCF-7 Cells Metabolism.
    Wenping Wang, Irene Liparulo, Nicola Rizzardi, Paola Bolignano, Natalia Calonghi, Christian Bergamini, Romana Fato.
      Mitochondrial dysfunction plays a significant role in the metabolic flexibility of cancer cells. This study aimed to investigate the metabolic alterations due to Coenzyme Q depletion in MCF-7 cells.
    METHOD: The Coenzyme Q depletion was induced by competitively inhibiting with 4-nitrobenzoate the coq2 enzyme, which catalyzes one of the final reactions in the biosynthetic pathway of CoQ. The bioenergetic and metabolic characteristics of control and coenzyme Q depleted cells were investigated using polarographic and spectroscopic assays. The effect of CoQ depletion on cell growth was analyzed in different metabolic conditions.
    RESULTS: we showed that cancer cells could cope from energetic and oxidative stress due to mitochondrial dysfunction by reshaping their metabolism. In CoQ depleted cells, the glycolysis was upregulated together with increased glucose consumption, overexpression of GLUT1 and GLUT3, as well as activation of pyruvate kinase (PK). Moreover, the lactate secretion rate was reduced, suggesting that the pyruvate flux was redirected, toward anabolic pathways. Finally, we found a different expression pattern in enzymes involved in glutamine metabolism, and TCA cycle in CoQ depleted cells in comparison to controls.
    CONCLUSION: This work elucidated the metabolic alterations in CoQ-depleted cells and provided an insightful understanding of cancer metabolism targeting.
    Keywords:  bioenergetics; cancer metabolism targeting; coenzyme Q; glutamine metabolism; glycolysis; metabolic reprogramming; mitochondrial dysfunction; spheroids
    DOI:  https://doi.org/10.3390/ijms22010198
  3. Cell Metab. 2020 Dec 17. pii: S1550-4131(20)30660-4. [Epub ahead of print]
    High Fructose Drives the Serine Synthesis Pathway in Acute Myeloid Leukemic Cells.
    Sangmoo Jeong, Angela Maria Savino, Rachel Chirayil, Ersilia Barin, Yuanming Cheng, Sun-Mi Park, Alexandra Schurer, Edouard Mullarky, Lewis C Cantley, Michael G Kharas, Kayvan R Keshari.
      A significant increase in dietary fructose consumption has been implicated as a potential driver of cancer. Metabolic adaptation of cancer cells to utilize fructose confers advantages for their malignant growth, but compelling therapeutic targets have not been identified. Here, we show that fructose metabolism of leukemic cells can be inhibited by targeting the de novo serine synthesis pathway (SSP). Leukemic cells, unlike their normal counterparts, become significantly dependent on the SSP in fructose-rich conditions as compared to glucose-rich conditions. This metabolic program is mediated by the ratio of redox cofactors, NAD+/NADH, and the increased SSP flux is beneficial for generating alpha-ketoglutarate from glutamine, which allows leukemic cells to proliferate even in the absence of glucose. Inhibition of PHGDH, a rate-limiting enzyme in the SSP, dramatically reduces leukemia engraftment in mice in the presence of high fructose, confirming the essential role of the SSP in the metabolic plasticity of leukemic cells.
    Keywords:  in vivo isotope tracing; metabolic flux; redox; serine synthesis pathway
    DOI:  https://doi.org/10.1016/j.cmet.2020.12.005
  4. Cell Metab. 2020 Dec 08. pii: S1550-4131(20)30655-0. [Epub ahead of print]
    Reductive TCA cycle metabolism fuels glutamine- and glucose-stimulated insulin secretion.
    Guo-Fang Zhang, Mette V Jensen, Sarah M Gray, Kimberley El, You Wang, Danhong Lu, Thomas C Becker, Jonathan E Campbell, Christopher B Newgard.
      Metabolic fuels regulate insulin secretion by generating second messengers that drive insulin granule exocytosis, but the biochemical pathways involved are incompletely understood. Here we demonstrate that stimulation of rat insulinoma cells or primary rat islets with glucose or glutamine + 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (Gln + BCH) induces reductive, "counter-clockwise" tricarboxylic acid (TCA) cycle flux of glutamine to citrate. Molecular or pharmacologic suppression of isocitrate dehydrogenase-2 (IDH2), which catalyzes reductive carboxylation of 2-ketoglutarate to isocitrate, results in impairment of glucose- and Gln + BCH-stimulated reductive TCA cycle flux, lowering of NADPH levels, and inhibition of insulin secretion. Pharmacologic suppression of IDH2 also inhibits insulin secretion in living mice. Reductive TCA cycle flux has been proposed as a mechanism for generation of biomass in cancer cells. Here we demonstrate that reductive TCA cycle flux also produces stimulus-secretion coupling factors that regulate insulin secretion, including in non-dividing cells.
    Keywords:  NADPH; anaplerosis; insulin secretion; isocitrate dehydrogenase-2; metabolic flux; pancreatic islet β cells; reductive TCA cycle; stable isotopes
    DOI:  https://doi.org/10.1016/j.cmet.2020.11.020
  5. Cell Metab. 2020 Dec 17. pii: S1550-4131(20)30662-8. [Epub ahead of print]
    Non-canonical Glutamate-Cysteine Ligase Activity Protects against Ferroptosis.
    Yun Pyo Kang, Andrea Mockabee-Macias, Chang Jiang, Aimee Falzone, Nicolas Prieto-Farigua, Everett Stone, Isaac S Harris, Gina M DeNicola.
      Cysteine is required for maintaining cellular redox homeostasis in both normal and transformed cells. Deprivation of cysteine induces the iron-dependent form of cell death known as ferroptosis; however, the metabolic consequences of cysteine starvation beyond impairment of glutathione synthesis are poorly characterized. Here, we find that cystine starvation of non-small-cell lung cancer cell lines induces an unexpected accumulation of γ-glutamyl-peptides, which are produced due to a non-canonical activity of glutamate-cysteine ligase catalytic subunit (GCLC). This activity is enriched in cell lines with high levels of NRF2, a key transcriptional regulator of GCLC, but is also inducible in healthy murine tissues following cysteine limitation. γ-glutamyl-peptide synthesis limits the accumulation of glutamate, thereby protecting against ferroptosis. These results indicate that GCLC has a glutathione-independent, non-canonical role in the protection against ferroptosis by maintaining glutamate homeostasis under cystine starvation.
    Keywords:  GCLC; NRF2; cysteine; cystine; ferroptosis; glutamate; γ-glutamyl
    DOI:  https://doi.org/10.1016/j.cmet.2020.12.007
  6. J Clin Med. 2020 Dec 18. pii: E4094. [Epub ahead of print]9(12):
    Non-Invasive Human Embryo Metabolic Assessment as a Developmental Criterion.
    Marjan Motiei, Katerina Vaculikova, Andrea Cela, Katerina Tvrdonova, Reza Khalili, David Rumpik, Tatana Rumpikova, Zdenek Glatz, Tomas Saha.
      The selection of a highly-viable single embryo in assisted reproductive technology requires an acceptable predictive method in order to reduce the multiple pregnancy rate and increase the success rate. In this study, the metabolomic profiling of growing and impaired embryos was assessed on the fifth day of fertilization using capillary electrophoresis in order to find a relationship between the profiling and embryo development, and then to provide a mechanistic insight into the appearance/depletion of the metabolites. This unique qualitative technique exhibited the appearance of most non-essential amino acids and lactate, and depleting the serine, alanyl-glutamine and pyruvate in such a manner that the embryos impaired in their development secreted a considerably higher level of lactate and consumed a significantly higher amount of alanyl-glutamine. The different significant ratios of metabolomic depletion/appearance between the embryos confirm their potential for the improvement of the prospective selection of the developed single embryos, and also suggest the fact that pyruvate and alanyl-glutamine are the most critical ATP suppliers on the fifth day of blastocyst development.
    Keywords:  capillary electrophoresis; culture media; embryo development; metabolomics
    DOI:  https://doi.org/10.3390/jcm9124094
  7. J Dairy Sci. 2020 Dec 22. pii: S0022-0302(20)31045-6. [Epub ahead of print]
    Glutamine pretreatment protects bovine mammary epithelial cells from inflammation and oxidative stress induced by γ-d-glutamyl-meso-diaminopimelic acid (iE-DAP).
    Xiaoye Cheng, Zain-Ui Aabdin, Yan Wang, Nana Ma, Hongyu Dai, Xiaoli Shi, Xiangzhen Shen.
      Glutamine (GLN) has many types of biological activity in rats, including anti-inflammatory, antioxidative stress, and anti-apoptosis effects. However, little is known about the effects of GLN on bovine mammary epithelial cells (BMEC). γ-d-Glutamyl-meso-diaminopimelic acid (iE-DAP) is a cell wall peptidoglycan component of gram-negative bacteria that can be recognized by the intracellular receptor nucleotide-binding oligomerization domain-containing protein 1 (NOD1) and can cause bovine mastitis. The goal of the present study was to investigate whether GLN protects BMEC from iE-DAP-induced inflammation, oxidative stress, and apoptosis. We cultured BMEC in a GLN-free medium for 24 h and then separated them into 4 groups: cells treated with 1× PBS for 26 or 32 h (control); cells stimulated by 10 μg/mL iE-DAP for 2 or 8 h (2- or 8-h iE-DAP); cells pretreated with 8 or 4 mM GLN for 24 h followed by 2 or 8 h of 1× PBS treatment (8 or 4 mM GLN); and cells pretreated with 8 or 4 mM GLN for 24 h followed by 2 or 8 h of iE-DAP treatment (DG). In the 2-h iE-DAP group, when levels of inflammation peaked, iE-DAP treatment increased both the mRNA and protein expression of NOD1, inhibitor of nuclear factor-κB (NFKBIA, IκB), and nuclear factor-κB subunit p65 (RELA, NF-κB p65), as well as the mRNA expression of IL6 and IL8 and levels of IL-6 and tumor necrosis factor-α in cell culture supernatants. In contrast, 8 mM GLN pretreatment inhibited the mRNA and protein expression of inflammatory-related factors by suppressing the NOD1/NF-κB pathway. In the 8-h iE-DAP group, iE-DAP treatment decreased the mRNA and protein expression of extracellular regulated kinase (Erk, ERK) and nuclear factor erythroid 2-associated factor2 (NFE2L2, Nrf2), as well as the mRNA expression of superoxide dismutase 1 (SOD1), catalase (CAT), coenzyme II oxidoreductase 1 (NQO1), and heme oxygenase 1 (HMOX1, HO1). In addition, iE-DAP treatment increased the expression of malondialdehyde in BMEC when oxidative stress levels peaked. Interestingly, 4 mM GLN pretreatment induced the mRNA and protein expression of antioxidative stress-related factors and inhibited the expression of reactive oxygen species in BMEC by promoting the ERK/Nrf2 pathway. Moreover, GLN reduced apoptosis caused by inflammation and oxidative stress in BMEC. This is the first report showing that GLN protects against iE-DAP-induced inflammation and oxidative stress via the NOD1/NF-κB and ERK/Nrf2 pathways in BMEC.
    Keywords:  anti-apoptosis; anti-inflammatory; antioxidative stress; glutamine
    DOI:  https://doi.org/10.3168/jds.2020-18402
  8. Free Radic Biol Med. 2020 Dec 23. pii: S0891-5849(20)31675-0. [Epub ahead of print]163 196-209
    Ascorbate kills breast cancer cells by rewiring metabolism via redox imbalance and energy crisis.
    Ali Ghanem, Anna Maria Melzer, Esther Zaal, Laura Neises, Danny Baltissen, Omar Matar, Hannah Glennemeier-Marke, Fadi Almouhanna, Jannick Theobald, Mohamed A Abu El Maaty, Celia Berkers, Stefan Wölfl.
      The idea to use megadoses of ascorbate (vitamin C) for cancer treatment has recently been revived. Despite clear efficacy in animal experimentation, our understanding of the cellular and molecular mechanisms of this treatment is still limited and suggests a combined oxidative and metabolic mechanism behind the selective cytotoxicity of ascorbate towards cancerous cells. To gain more insight into the cellular effects of high doses of ascorbate, we performed a detailed analysis of metabolic changes and cell survival of both luminal and basal-like breast cancer cells treated with ascorbate and revealed a distinctive metabolic shift virtually reversing the Warburg effect and triggering a severe disruption of redox homeostasis. High doses of ascorbate were cytotoxic against MCF7 and MDA-MB231 cells representing luminal and basal-like breast cancer phenotypes. Cell death was dependent on ascorbate-induced oxidative stress and accumulation of ROS, DNA damage, and depletion of essential intracellular co-factors including NAD+/NADH, associated with a multifaceted metabolic rewiring. This included a sharp disruption of glycolysis at the triose phosphate level, a rapid drop in ATP levels, and redirection of metabolites toward lipid droplet accumulation and increased metabolites and enzymatic activity in the pentose phosphate pathway (PPP). High doses of ascorbate also inhibited the TCA cycle and increased oxygen consumption. Together the severe disruptions of the intracellular metabolic homeostasis on multiple levels "redox crisis and energetic catastrophe" consequently trigger a rapid irreversible cell death.
    Keywords:  Ascorboic acid; Breast cancer; Cancer; Cancer metabolism; Metabolic rewiring; Oxidative burst; Oxidative stress; Peroxide; Redox; Reversing warburg effect; Targetting cancer metabolism; Vitamin C
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2020.12.012
  9. Int J Mol Sci. 2020 Dec 22. pii: E23. [Epub ahead of print]22(1):
    Amino Acid Transporters Are a Vital Focal Point in the Control of mTORC1 Signaling and Cancer.
    Yann Cormerais, Milica Vučetić, Scott K Parks, Jacques Pouyssegur.
      The mechanistic target of rapamycin complex 1 (mTORC1) integrates signals from growth factors and nutrients to control biosynthetic processes, including protein, lipid, and nucleic acid synthesis. Dysregulation in the mTORC1 network underlies a wide array of pathological states, including metabolic diseases, neurological disorders, and cancer. Tumor cells are characterized by uncontrolled growth and proliferation due to a reduced dependency on exogenous growth factors. The genetic events underlying this property, such as mutations in the PI3K-Akt and Ras-Erk signaling networks, lead to constitutive activation of mTORC1 in nearly all human cancer lineages. Aberrant activation of mTORC1 has been shown to play a key role for both anabolic tumor growth and resistance to targeted therapeutics. While displaying a growth factor-independent mTORC1 activity and proliferation, tumors cells remain dependent on exogenous nutrients such as amino acids (AAs). AAs are an essential class of nutrients that are obligatory for the survival of any cell. Known as the building blocks of proteins, AAs also act as essential metabolites for numerous biosynthetic processes such as fatty acids, membrane lipids and nucleotides synthesis, as well as for maintaining redox homeostasis. In most tumor types, mTORC1 activity is particularly sensitive to intracellular AA levels. This dependency, therefore, creates a targetable vulnerability point as cancer cells become dependent on AA transporters to sustain their homeostasis. The following review will discuss the role of AA transporters for mTORC1 signaling in cancer cells and their potential as therapeutic drug targets.
    Keywords:  ASCT2; LAT1; SNAT2; amino acid transporters; cancer; growth factors; mTORC1; nutrients; xCT
    DOI:  https://doi.org/10.3390/ijms22010023
  10. Cancer Manag Res. 2020 ;12 13259-13271
    Regulation of Autophagy by Glycolysis in Cancer.
    Ying Chu, Yi Chang, Wei Lu, Xiumei Sheng, Shengjun Wang, Huaxi Xu, Jie Ma.
      Autophagy is a critical cellular process that generally protects cells and organisms from harsh environment, including limitations in adenosine triphosphate (ATP) availability or a lack of essential nutrients. Metabolic reprogramming, a hallmark of cancer, has recently gained interest in the area of cancer therapy. It is well known that cancer cells prefer to utilize glycolysis rather than oxidative phosphorylation (OXPHOS) as their major energy source to rapidly generate ATP even in aerobic environment called the Warburg effect. Both autophagy and glycolysis play essential roles in pathological processes of cancer. A mechanism of metabolic changes to drive tumor progression is its ability to regulate autophagy. This review will elucidate the role and the mechanism of glycolysis in regulating autophagy during tumor growth. Indeed, understanding how glycolysis can modulate cellular autophagy will enable more effective combinatorial therapeutic strategies.
    Keywords:  autophagy; glycolysis; lactate; lung cancer; metabolism
    DOI:  https://doi.org/10.2147/CMAR.S279672
  11. Metabolites. 2020 Dec 22. pii: E1. [Epub ahead of print]11(1):
    Metabolomic Analysis to Elucidate Mechanisms of Sunitinib Resistance in Renal Cell Carcinoma.
    Tomonori Sato, Yoshihide Kawasaki, Masamitsu Maekawa, Shinya Takasaki, Kento Morozumi, Masahiko Sato, Shuichi Shimada, Naoki Kawamorita, Shinichi Yamashita, Koji Mitsuzuka, Nariyasu Mano, Akihiro Ito.
      Metabolomics analysis possibly identifies new therapeutic targets in treatment resistance by measuring changes in metabolites accompanying cancer progression. We previously conducted a global metabolomics (G-Met) study of renal cell carcinoma (RCC) and identified metabolites that may be involved in sunitinib resistance in RCC. Here, we aimed to elucidate possible mechanisms of sunitinib resistance in RCC through intracellular metabolites. We established sunitinib-resistant and control RCC cell lines from tumor tissues of RCC cell (786-O)-injected mice. We also quantified characteristic metabolites identified in our G-Met study to compare intracellular metabolism between the two cell lines using liquid chromatography-mass spectrometry. The established sunitinib-resistant RCC cell line demonstrated significantly desuppressed protein kinase B (Akt) and mesenchymal-to-epithelial transition (MET) phosphorylation compared with the control RCC cell line under sunitinib exposure. Among identified metabolites, glutamine, glutamic acid, and α-KG (involved in glutamine uptake into the tricarboxylic acid (TCA) cycle for energy metabolism); fructose 6-phosphate, D-sedoheptulose 7-phosphate, and glucose 1-phosphate (involved in increased glycolysis and its intermediate metabolites); and glutathione and myoinositol (antioxidant effects) were significantly increased in the sunitinib-resistant RCC cell line. Particularly, glutamine transporter (SLC1A5) expression was significantly increased in sunitinib-resistant RCC cells compared with control cells. In this study, we demonstrated energy metabolism with glutamine uptake and glycolysis upregulation, as well as antioxidant activity, was also associated with sunitinib resistance in RCC cells.
    Keywords:  glutamine; metabolomics; renal cell carcinoma; resistance; sunitinib
    DOI:  https://doi.org/10.3390/metabo11010001
  12. Curr Opin Biotechnol. 2020 Dec 23. pii: S0958-1669(20)30180-4. [Epub ahead of print]68 181-185
    Illuminating the cross-talk between tumor metabolism and immunity in IDH-mutated cancers.
    Julie Leca, Jerome Fortin, Tak W Mak.
      Mutations in the genes encoding isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) are key drivers of diverse cancers, including gliomas and hematological malignancies. IDH mutations cause neomorphic enzymatic activity that results in the production of the oncometabolite 2-hydroxyglutarate (2-HG). In addition to 2-HG's well-known effects on tumor cells themselves, it has become increasingly clear that 2-HG directly influences the tumor microenvironment (TME). In particular, the non-cell-autonomous impact of 2-HG on the immune system likely plays a major role in shaping disease development and response to therapy. It is therefore critical to understand how IDH mutations affect the metabolism, epigenetics, and functions of tumor-infiltrating immune cells. Such knowledge may point towards new therapeutic approaches to treat IDH-mutant cancers.
    DOI:  https://doi.org/10.1016/j.copbio.2020.11.013
  13. Prostate. 2020 Dec 24.
    Prostate cancer C5a receptor expression and augmentation of cancer cell proliferation, invasion, and PD-L1 expression by C5a.
    Ryuji Imamura, Saki Kitagawa, Tatsuko Kubo, Atsushi Irie, Toru Kariu, Masakazu Yoneda, Tomomi Kamba, Takahisa Imamura.
       BACKGROUND: The treatment of castration-resistant prostate cancer (CRPC) is a urological issue. Recent studies have revealed cancer promotion via the C5a-C5a receptor (C5aR) system. To establish a new therapeutic target for CRPC, we investigated an association of the system with CRPC progression and evasion from the antitumor immune responses.
    METHODS: C5aR and PD-L1 were immunostained in the prostate cancer (PC) tissues. The relationship of PC C5aR expression to clinicopathological parameters was analyzed. CRPC cell lines were examined for C5aR expression by real-time reverse transcription polymerase chain reaction, immunoblotting, and flow cytometry. C5a effects were examined on CRPC cell glutamine consumption, proliferation, invasion, and PD-L1 expression.
    RESULTS: PC cells expressed C5aR in 83 of the 161 patients (52%) and in three of the six CRPC patients. Basal cells, but not luminal cells, of noncancerous prostate glands expressed C5aR. Three CRPC cell lines expressed C5aR. C5a increased CRPC cell glutamine consumption 2.1-fold, proliferation 1.3-1.6-fold, and invasion 2-3-fold in a C5a-concentration and a C5aR-dependent manner. High expression of C5aR did not relate to the PC patients' clinical parameters but the PD-L1-positive rate was higher in the C5aR high-expression patients (37.5%) compared to low- or no expression patients (17.8%), and double-positive PC cells were present. C5a increased CRPC cell PD-L1 production 1.4-fold and cell-surface expression 2.6-fold.
    CONCLUSIONS: C5aR expression of PC cells in patients' tissues and C5a augmentation of C5aR-dependent CRPC proliferation, invasion, and PD-L1 expression suggested participation of the C5a-C5aR system in CRPC promotion and evasion from antitumor immune responses. Targeting this signaling pathway may provide a useful therapeutic option for CRPC.
    Keywords:  CD88; CRPC; PD-L1; glutamine; growth; invasion
    DOI:  https://doi.org/10.1002/pros.24090
  14. Antioxidants (Basel). 2020 Dec 28. pii: E19. [Epub ahead of print]10(1):
    Interplay among Oxidative Stress, Methylglyoxal Pathway and S-Glutathionylation.
    Lidia de Bari, Andrea Scirè, Cristina Minnelli, Laura Cianfruglia, Miklos Peter Kalapos, Tatiana Armeni.
      Reactive oxygen species (ROS) are produced constantly inside the cells as a consequence of nutrient catabolism. The balance between ROS production and elimination allows to maintain cell redox homeostasis and biological functions, avoiding the occurrence of oxidative distress causing irreversible oxidative damages. A fundamental player in this fine balance is reduced glutathione (GSH), required for the scavenging of ROS as well as of the reactive 2-oxoaldehydes methylglyoxal (MGO). MGO is a cytotoxic compound formed constitutively as byproduct of nutrient catabolism, and in particular of glycolysis, detoxified in a GSH-dependent manner by the glyoxalase pathway consisting in glyoxalase I and glyoxalase II reactions. A physiological increase in ROS production (oxidative eustress, OxeS) is promptly signaled by the decrease of cellular GSH/GSSG ratio which can induce the reversible S-glutathionylation of key proteins aimed at restoring the redox balance. An increase in MGO level also occurs under oxidative stress (OxS) conditions probably due to several events among which the decrease in GSH level and/or the bottleneck of glycolysis caused by the reversible S-glutathionylation and inhibition of glyceraldehyde-3-phosphate dehydrogenase. In the present review, it is shown how MGO can play a role as a stress signaling molecule in response to OxeS, contributing to the coordination of cell metabolism with gene expression by the glycation of specific proteins. Moreover, it is highlighted how the products of MGO metabolism, S-D-lactoylglutathione (SLG) and D-lactate, which can be taken up and metabolized by mitochondria, could play important roles in cell response to OxS, contributing to cytosol-mitochondria crosstalk, cytosolic and mitochondrial GSH pools, energy production, and the restoration of the GSH/GSSG ratio. The role for SLG and glyoxalase II in the regulation of protein function through S-glutathionylation under OxS conditions is also discussed. Overall, the data reported here stress the need for further studies aimed at understanding what role the evolutionary-conserved MGO formation and metabolism can play in cell signaling and response to OxS conditions, the aberration of which may importantly contribute to the pathogenesis of diseases associated to elevated OxS.
    Keywords:  S-D-lactoylglutathione; glutathione; glutathionylation; glyoxalase system; methylglyoxal; mitochondria; redox signaling
    DOI:  https://doi.org/10.3390/antiox10010019
  15. Mol Cancer Ther. 2020 Dec 23. pii: molcanther.0430.2020. [Epub ahead of print]
    The glutaminase inhibitor CB-839 (Telaglenastat) enhances the anti-melanoma activity of T cell mediated immunotherapies.
    Sruthy Varghese, Snigdha Pramanik, Leila J Williams, Hannah R Hodges, Courtney W Hudgens, Grant M Fischer, Catherine K Luo, Barbara Knighton, Lin Tan, Philip L Lorenzi, Andrew L MacKinnon, Jennifer L McQuade, Yared Hailemichael, Jason Roszik, Weiyi Peng, Y N Vashisht Gopal.
      Immune checkpoint inhibitors and adoptive tumor-infiltrating lymphocyte (TIL) therapies have profoundly improved the survival of melanoma patients. However, a majority of patients do not respond to these agents, and many responders experience disease relapse. While numerous innovative treatments are being explored to offset the limitations of these agents, novel therapeutic combinations with immunotherapies have the potential to improve patient responses. In this study, we evaluated the anti-melanoma activity of immunotherapy combinations with Telaglenastat (CB-839), a potent glutaminase inhibitor (GLSi) that has favorable systemic tolerance. In in vitro TIL:tumor co-culture studies, CB-839 treatment improved the cytotoxic activity of autologous TILs on patient-derived melanoma cells. CB-839 treatment decreased the conversion of glutamine to alpha-ketoglutarate (αKGA) more potently in tumor cells versus TILs in these co-cultures. These results suggest that CB-839 may improve immune function in a tumor microenvironment by differentially altering tumor and immune cell metabolism. In vivo CB-839 treatment activated melanoma antigen-specific T cells, and improved their tumor killing activity in an immune-competent mouse model of adoptive T cell therapy. Additionally, combination of CB-839 with anti-PD1 or anti-CTLA4 antibodies increased tumor infiltration by effector T cells and improved the anti-tumor activity of these checkpoint inhibitors in a high mutation burden mouse melanoma model. Responsiveness to these treatments was also accompanied by an increase of interferon gamma (IFNγ)-associated gene expression in the tumors. Together, these results provide a strong rationale for combining CB-839 with immune therapies to improve efficacy of these treatments against melanoma.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-20-0430
  16. Mech Ageing Dev. 2020 Dec 28. pii: S0047-6374(20)30224-4. [Epub ahead of print] 111428
    Effects of cellular senescence on metabolic pathways in non-immune and immune cells.
    Daniela Frasca, Yara Bou Saada, Denisse Garcia, Bertrand Friguet.
      Many cellular stresses induce cellular senescence and the irreversible arrest of cell proliferation in different cell types. Although blocked in their capacity to divide, senescent cells are metabolically active and are characterized by a different metabolic phenotype as compared to non-senescent cells. Changes observed in senescent cells depend from the cell type and lead to an adaptative flexibility in the type of metabolism. This metabolic reprogramming is needed to cope with survival and with the energetic demands of the senescent program that include the increased secretion of senescence-associated secretory phenotype factors.
    Keywords:  Cellular senescence; immune cells; metabolism; non-immune cells
    DOI:  https://doi.org/10.1016/j.mad.2020.111428
  17. Int J Cancer. 2020 Dec 24.
    Abrogating GPT2 in triple negative breast cancer inhibits tumor growth and promotes autophagy.
    Devina Mitra, Silvia Vega-Rubin-de-Celis, Nadine Royla, Stephan Bernhardt, Heike Wilhelm, Nooraldeen Tarade, Gernot Poschet, Michael Buettner, Ilona Binenbaum, Simone Borgoni, Martina Vetter, Eva Johanna Kantelhardt, Christoph Thomssen, Aristotelis Chatziioannou, Rüdiger Hell, Stefan Kempa, Karin Müller-Decker, Stefan Wiemann.
      Uncontrolled proliferation and altered metabolic reprogramming are hallmarks of cancer. Active glycolysis and glutaminolysis are characteristic features of these hallmarks and required for tumorigenesis. A fine balance between cancer metabolism and autophagy is a prerequisite of homeostasis within cancer cells. Here we show that glutamate pyruvate transaminase 2 (GPT2), which serves as a pivot between glycolysis and glutaminolysis, is highly upregulated in aggressive breast cancers, particularly the triple negative breast cancer (TNBC) subtype. Abrogation of this enzyme results in decreased TCA cycle intermediates, which promotes the rewiring of glucose carbon atoms and alterations in nutrient levels. Concordantly, loss of GPT2 results in an impairment of mechanistic target of rapamycin complex 1 (mTORC1) activity as well as the induction of autophagy. Furthermore, in vivo xenografts studies have shown that autophagy induction correlates with decreased tumor growth and that markers of induced autophagy correlate with low GPT2 levels in patient samples. Taken together, these findings indicate that cancer cells have a close network between metabolic and nutrient sensing pathways necessary to sustain tumorigenesis, and that aminotransferase reactions play an important role in maintaining this balance.
    Keywords:  Autophagy; Breast Cancer; Cancer metabolism; GPT2; mTORC1
    DOI:  https://doi.org/10.1002/ijc.33456
  18. Front Med. 2021 Jan 02.
    Proteins moonlighting in tumor metabolism and epigenetics.
    Lei Lv, Qunying Lei.
      Cancer development is a complicated process controlled by the interplay of multiple signaling pathways and restrained by oxygen and nutrient accessibility in the tumor microenvironment. High plasticity in using diverse nutrients to adapt to metabolic stress is one of the hallmarks of cancer cells. To respond to nutrient stress and to meet the requirements for rapid cell proliferation, cancer cells reprogram metabolic pathways to take up more glucose and coordinate the production of energy and intermediates for biosynthesis. Such actions involve gene expression and activity regulation by the moonlighting function of oncoproteins and metabolic enzymes. The signal - moonlighting protein - metabolism axis facilitates the adaptation of tumor cells under varying environment conditions and can be therapeutically targeted for cancer treatment.
    Keywords:  epigenetics; moonlighting function; tumor metabolism
    DOI:  https://doi.org/10.1007/s11684-020-0818-1
  19. Bone. 2020 Dec 28. pii: S8756-3282(20)30624-4. [Epub ahead of print] 115836
    Glutamine metabolite α-ketoglutarate acts as an epigenetic co-factor to interfere with osteoclast differentiation.
    Sangyong Lee, Hyuk Soon Kim, Myoung Jun Kim, Keun Young Min, Wahn Soo Choi, Jueng Soo You.
      Osteoclasts (OCs) have been well-known involved in the exacerbation of bone-related diseases. However, the role of metabolites on osteoclastogenesis has not been well characterized. Herein, we found osteoclastogenesis was negatively regulated by α-ketoglutarate (αKG) in vitro and in vivo (C57BL/6 mouse). Kinetic transcriptome analysis revealed the upregulation of solute carrier family 7 member 11 (Slc7a11), a subunit of the cysteine/glutamate antiporter, as well as the downregulation of typical OC maker genes through αKG treatment. Given that Slc7a11 could control ROS level through glutathione import, we measured intracellular ROS, then RANKL-induced ROS production was inhibited by αKG. Notably, we highlight that αKG plays an epigenetic co-factor at the Slc7a11 promoter by demethylating repressive histone H3K9 methylation and simultaneously increasing the nuclear factor erythroid 2-related factor (Nrf2) binding, a critical transcription factor through chromatin immunoprecipitation (ChIP) analysis. Together, we suggested that αKG could be a therapeutic strategy for OC activated diseases.
    Keywords:  Epigenetics; Nrf2; Osteoclast; Osteoporosis; Slc7a11; alpha-ketoglutarate
    DOI:  https://doi.org/10.1016/j.bone.2020.115836
  20. Front Pharmacol. 2020 ;11 600561
    Exploration the Mechanism of Doxorubicin-Induced Heart Failure in Rats by Integration of Proteomics and Metabolomics Data.
    Yu Yuan, Simiao Fan, Lexin Shu, Wei Huang, Lijuan Xie, Chenghao Bi, Hongxin Yu, Yuming Wang, Yubo Li.
      Heart failure is a common systemic disease with high morbidity and mortality worldwide. Doxorubicin (DOX) is a commonly used anthracycline broad-spectrum antitumor antibiotic with strong antitumor effect and definite curative effect. However, cardiotoxicity is the adverse reaction of drug dose cumulative toxicity, but the mechanism is still unclear. In this study, proteomics and metabonomics techniques were used to analyze the tissue and plasma of DOX-induced heart failure (HF) in rats and to clarify the molecular mechanism of the harmful effects of DOX on cardiac metabolism and function in rats from a new point of view. The results showed that a total of 278 proteins with significant changes were identified by quantitative proteomic analysis, of which 118 proteins were significantly upregulated and 160 proteins were significantly downregulated in myocardial tissue. In the metabonomic analysis, 21 biomarkers such as L-octanoylcarnitine, alpha-ketoglutarate, glutamine, creatine, and sphingosine were detected. Correlation analysis showed that DOX-induced HF mainly affected phenylalanine, tyrosine, and tryptophan biosynthesis, D-glutamine and D-glutamate metabolism, phenylalanine metabolism, biosynthesis of unsaturated fatty acids, and other metabolic pathways, suggesting abnormal amino acid metabolism, fatty acid metabolism, and glycerol phospholipid metabolism. It is worth noting that we have found the key upstream target of DOX-induced HF, PTP1B, which inhibits the expression of HIF-1α by inhibiting the phosphorylation of IRS, leading to disorders of fatty acid metabolism and glycolysis, which together with the decrease of Nrf2, SOD, Cytc, and AK4 proteins lead to oxidative stress. Therefore, we think that PTP1B may play an important role in the development of heart failure induced by doxorubicin and can be used as a potential target for the treatment of heart failure.
    Keywords:  doxorubicin; heart failure; metabonomics; protein tyrosine-protein phosphatase non-receptor type 1; proteomics
    DOI:  https://doi.org/10.3389/fphar.2020.600561
  21. Int J Oncol. 2020 Nov 25.
    Critical role of mTOR in regulating aerobic glycolysis in carcinogenesis (Review).
    Hui Fan, Yuanyuan Wu, Suyun Yu, Xiaoman Li, Aiyun Wang, Shijun Wang, Wenxing Chen, Yin Lu.
      Mammalian target of rapamycin (mTOR) serves an important role in regulating various biological processes, including cell proliferation, metabolism, apoptosis and autophagy. Among these processes, energy metabolism is the dominant process. The metabolism of not only amino acids, fatty acids and lipids, but also that of nucleotides and glucose has been indicated to be regulated by mTOR. Aerobic glycolysis, which is a specific form of glucose metabolism, is prevalent in carcinomas, and it has been considered to be a potential target for cancer therapy. In reviewing the complexity of the mTOR pathway, it is important to elucidate the central role and detailed pathway via which mTOR regulates glycolysis. In the present study, the complex mechanisms via which mTOR regulates aerobic glycolysis were comprehensively reviewed to highlight the potential of drug development via targeting the molecules associated with mTOR and glycolysis and to further provide strategies for the clinical treatment of cancer.
    DOI:  https://doi.org/10.3892/ijo.2020.5152
  22. Front Oncol. 2020 ;10 599915
    How Autophagy Shapes the Tumor Microenvironment in Ovarian Cancer.
    Alessandra Ferraresi, Carlo Girone, Andrea Esposito, Chiara Vidoni, Letizia Vallino, Eleonora Secomandi, Danny N Dhanasekaran, Ciro Isidoro.
      Ovarian cancer (OC) is characterized by a high mortality rate due to the late diagnosis and the elevated metastatic potential. Autophagy, a lysosomal-driven catabolic process, contributes to the macromolecular turnover, cell homeostasis, and survival, and as such, it represents a pathway targetable for anti-cancer therapies. It is now recognized that the vascularization and the cellular composition of the tumor microenvironment influence the development and progression of OC by controlling the availability of nutrients, oxygen, growth factors, and inflammatory and immune-regulatory soluble factors that ultimately impinge on autophagy regulation in cancer cells. An increasing body of evidence indicates that OC carcinogenesis is associated, at least in the early stages, to insufficient autophagy. On the other hand, when the tumor is already established, autophagy activation provides a survival advantage to the cancer cells that face metabolic stress and protects from the macromolecules and organelles damages induced by chemo- and radiotherapy. Additionally, upregulation of autophagy may lead cancer cells to a non-proliferative dormant state that protects the cells from toxic injuries while preserving their stem-like properties. Further to complicate the picture, autophagy is deregulated also in stromal cells. Thus, changes in the tumor microenvironment reflect on the metabolic crosstalk between cancer and stromal cells impacting on their autophagy levels and, consequently, on cancer progression. Here, we present a brief overview of the role of autophagy in OC hallmarks, including tumor dormancy, chemoresistance, metastasis, and cell metabolism, with an emphasis on the bidirectional metabolic crosstalk between cancer cells and stromal cells in shaping the OC microenvironment.
    Keywords:  autophagy; cancer; cancer associated fibroblasts; cell metabolism; chemoresistance; cytokines; dormancy; inflammatory stroma
    DOI:  https://doi.org/10.3389/fonc.2020.599915
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