bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2021–11–21
twelve papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Metabolic Analysis of the Asparagine and Glutamine Dynamics in an Industrial CHO Fed-Batch Process.
  2. The Role of Succinic Acid Metabolism in Ovarian Cancer.
  3. DLST-dependence dictates metabolic heterogeneity in TCA-cycle usage among triple-negative breast cancer.
  4. Enhanced Antitumor Effect in Liver Cancer by Amino Acid Depletion-Induced Oxidative Stress.
  5. Folliculin impairs breast tumor growth by repressing TFE3-dependent induction of the Warburg effect and angiogenesis.
  6. Methionine synthase supports tumour tetrahydrofolate pools.
  7. The metabolic growth limitations of petite cells lacking the mitochondrial genome.
  8. Beyond mitophagy: mitochondrial-derived vesicles can get the job done!
  9. ROS/JNK/C-Jun Pathway is Involved in Chaetocin Induced Colorectal Cancer Cells Apoptosis and Macrophage Phagocytosis Enhancement.
  10. CRISPR screens unveil signal hubs for nutrient licensing of T cell immunity.
  11. Metabolic characterization and metabolism-score of tumor to predict the prognosis in prostate cancer.
  12. Cysteine exerts an essential role in maintaining intestinal integrity and function independent of glutathione.
  1. Biotechnol Bioeng. 2021 Nov 17.
    Metabolic Analysis of the Asparagine and Glutamine Dynamics in an Industrial CHO Fed-Batch Process.
    Brian James Kirsch, Sandra V Bennun, Adam Mendez, Amy S Johnson, Hongxia Wang, Haibo Qiu, Ning Li, Shawn M Lawrence, Hanne Bak, Michael J Betenbaugh.
      Chinese Hamster Ovary (CHO) cell lines are grown in cultures with varying asparagine and glutamine concentrations, but further study is needed to characterize the interplay between these amino acids. By following 13 C-glucose, 13 C-glutamine, and 13 C-asparagine tracers using metabolic flux analysis (MFA), CHO cell metabolism was characterized in an industrially relevant fed-batch process under glutamine supplemented and low glutamine conditions during early and late exponential growth. For both conditions MFA revealed glucose as the primary carbon source to the tricarboxylic acid (TCA) cycle followed by glutamine and asparagine as secondary sources. Early exponential phase CHO cells prefer glutamine over asparagine to support the TCA cycle under the glutamine supplemented condition, while asparagine was critical for TCA activity for the low glutamine condition. Overall TCA fluxes were similar for both conditions due to the trade-offs associated with reliance on glutamine and/or asparagine. However, glutamine supplementation increased fluxes to alanine, lactate and enrichment of glutathione, N-Acetyl-Glucosamine (NAG) and pyrimidine-containing-molecules. The late exponential phase exhibited reduced central carbon metabolism dominated by glucose, while lactate reincorporation and aspartate uptake were preferred over glutamine and asparagine. These 13 C studies demonstrate that metabolic flux is process time dependent and can be modulated by varying feed composition. This article is protected by copyright. All rights reserved.
    Keywords:   13C tracers; Chinese hamster ovary cells; Metabolic Flux Analysis (MFA); asparagine; fed-batch; glucose; glutamine; glutathione; metabolism; pyrimidine synthesis
    DOI:  https://doi.org/10.1002/bit.27993
  2. Front Oncol. 2021 ;11 769196
    The Role of Succinic Acid Metabolism in Ovarian Cancer.
    Lei Xia, Hairong Zhang, Xuezhen Wang, Xiaoyu Zhang, Ke Nie.
      Ovarian cancer is one of the most common malignancies and the highest mortality among gynecological malignancy. The standard therapy options for patients with ovarian cancer are cytoreductive surgery and chemotherapy, and although most patients do better with standard treatment, it is easy to relapse and be resistant to chemotherapy. Therefore, it is important to find new therapeutic strategies. More recently, metabolic reprogramming has been recognized as a hallmark of cancer and has become a potential target for tumor therapy. Mutations of metabolic enzymes are closely related to the development of ovarian cancer. The metabolic reprogramming of ovarian cancer not only provides energy to tumor cells, but also participates in various biological processes as signaling molecules. Succinic acid (SA) is an important metabolic intermediate involved in a number of metabolic pathways, such as TCA cycle and glutamine metabolism, and is also widely present in a variety of plants and vegetables. Studies show abnormal SA metabolism in many tumors and affect tumor formation through a variety of mechanisms. But the role of SA in ovarian cancer is less studied. This paper reviews the role of SA and its abnormal metabolic pathway in ovarian cancer.
    Keywords:  IDH; SDH; SUCNR1; glutamine; succinate acid
    DOI:  https://doi.org/10.3389/fonc.2021.769196
  3. Commun Biol. 2021 Nov 16. 4(1): 1289
    DLST-dependence dictates metabolic heterogeneity in TCA-cycle usage among triple-negative breast cancer.
    Ning Shen, Sovannarith Korm, Theodoros Karantanos, Dun Li, Xiaoyu Zhang, Eleni Ritou, Hanfei Xu, Andrew Lam, Justin English, Wei-Xing Zong, Ching-Ti Liu, Orian Shirihai, Hui Feng.
      Triple-negative breast cancer (TNBC) is traditionally considered a glycolytic tumor with a poor prognosis while lacking targeted therapies. Here we show that high expression of dihydrolipoamide S-succinyltransferase (DLST), a tricarboxylic acid (TCA) cycle enzyme, predicts poor overall and recurrence-free survival among TNBC patients. DLST depletion suppresses growth and induces death in subsets of human TNBC cell lines, which are capable of utilizing glutamine anaplerosis. Metabolomics profiling reveals significant changes in the TCA cycle and reactive oxygen species (ROS) related pathways for sensitive but not resistant TNBC cells. Consequently, DLST depletion in sensitive TNBC cells increases ROS levels while N-acetyl-L-cysteine partially rescues cell growth. Importantly, suppression of the TCA cycle through DLST depletion or CPI-613, a drug currently in clinical trials for treating other cancers, decreases the burden and invasion of these TNBC. Together, our data demonstrate differential TCA-cycle usage in TNBC and provide therapeutic implications for the DLST-dependent subsets.
    DOI:  https://doi.org/10.1038/s42003-021-02805-8
  4. Front Oncol. 2021 ;11 758549
    Enhanced Antitumor Effect in Liver Cancer by Amino Acid Depletion-Induced Oxidative Stress.
    Keiichiro Okuda, Atsushi Umemura, Seita Kataoka, Kota Yano, Aya Takahashi, Shinya Okishio, Hiroyoshi Taketani, Yuya Seko, Taichiro Nishikawa, Kanji Yamaguchi, Michihisa Moriguchi, Hayato Nakagawa, Yu Liu, Yasuhide Mitsumoto, Yoshihiro Kanbara, Toshihide Shima, Takeshi Okanoue, Yoshito Itoh.
      Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. HCC cells consume large amounts of glutamine to survive, but can adapt to glutamine depletion in the presence of an exogenous asparagine. L-asparaginase (ASNase) converts glutamine and asparagine to glutamate and aspartate, respectively, and has been used to treat leukemia. Here we examined the effects of ASNase treatment on HCC cells and explored the potential impact of combining ASNase with the tyrosine kinase inhibitor lenvatinib (Len) for HCC treatment. Cell viability and death of HCC cell lines treated with either Len or ASNase alone or with Len and ASNase combined were determined. We assessed mRNA and protein expression levels of glutamine synthetase (GS) and asparagine synthetase (ASNS) by real-time quantitative PCR and immunoblotting. The antitumor effect of the combination therapy relative to Len or ASNase monotherapy was also evaluated in a xenograft tumor mouse model. ASNase treatment inhibited growth of SNU387 and SNU398 HCC cells, which have low GS and high ASNS expression levels, respectively, but did not clearly inhibit growth of the other cell lines. Len plus ASNase combination therapy synergistically inhibited proliferation and induced oxidative stress leading to cell death of some HCC cells lines. However, cell death of Huh7 cells, which express ASCT2, an important glutamine transporter for cancer cells, was not affected by the combination treatment. In a xenograft model, Len combined with ASNase significantly attenuated tumor development relative to mice treated with Len or ASNase alone. ASNase-mediated targeting of two amino acids, glutamine and asparagine, which are indispensable for HCC survival, induces oxidative stress and can be a novel cancer treatment option that exerts a synergistic effect when used in combination with Len.
    Keywords:  L-asparaginase; asparagine; asparagine synthetase; glutamine; glutamine synthetase; lenvatinib; liver cancer; oxidative stress
    DOI:  https://doi.org/10.3389/fonc.2021.758549
  5. J Clin Invest. 2021 Nov 15. pii: e144871. [Epub ahead of print]131(22):
    Folliculin impairs breast tumor growth by repressing TFE3-dependent induction of the Warburg effect and angiogenesis.
    Leeanna El-Houjeiri, Marco Biondini, Mathieu Paquette, Helen Kuasne, Alain Pacis, Morag Park, Peter M Siegel, Arnim Pause.
      Growing tumors exist in metabolically compromised environments that require activation of multiple pathways to scavenge nutrients to support accelerated rates of growth. The folliculin (FLCN) tumor suppressor complex (FLCN, FNIP1, FNIP2) is implicated in the regulation of energy homeostasis via 2 metabolic master kinases: AMPK and mTORC1. Loss-of-function mutations of the FLCN tumor suppressor complex have only been reported in renal tumors in patients with the rare Birt-Hogg-Dube syndrome. Here, we revealed that FLCN, FNIP1, and FNIP2 are downregulated in many human cancers, including poor-prognosis invasive basal-like breast carcinomas where AMPK and TFE3 targets are activated compared with the luminal, less aggressive subtypes. FLCN loss in luminal breast cancer promoted tumor growth through TFE3 activation and subsequent induction of several pathways, including autophagy, lysosomal biogenesis, aerobic glycolysis, and angiogenesis. Strikingly, induction of aerobic glycolysis and angiogenesis in FLCN-deficient cells was dictated by the activation of the PGC-1α/HIF-1α pathway, which we showed to be TFE3 dependent, directly linking TFE3 to Warburg metabolic reprogramming and angiogenesis. Conversely, FLCN overexpression in invasive basal-like breast cancer models attenuated TFE3 nuclear localization, TFE3-dependent transcriptional activity, and tumor growth. These findings support a general role of a deregulated FLCN/TFE3 tumor suppressor pathway in human cancers.
    Keywords:  Angiogenesis; Breast cancer; Cancer; Metabolism
    DOI:  https://doi.org/10.1172/JCI144871
  6. Nat Metab. 2021 Nov;3(11): 1512-1520
    Methionine synthase supports tumour tetrahydrofolate pools.
    Jonathan M Ghergurovich, Xincheng Xu, Joshua Z Wang, Lifeng Yang, Rolf-Peter Ryseck, Lin Wang, Joshua D Rabinowitz.
      Mammalian cells require activated folates to generate nucleotides for growth and division. The most abundant circulating folate species is 5-methyl tetrahydrofolate (5-methyl-THF), which is used to synthesize methionine from homocysteine via the cobalamin-dependent enzyme methionine synthase (MTR). Cobalamin deficiency traps folates as 5-methyl-THF. Here, we show using isotope tracing that MTR is only a minor source of methionine in cell culture, tissues or xenografted tumours. Instead, MTR is required for cells to avoid folate trapping and assimilate 5-methyl-THF into other folate species. Under conditions of physiological extracellular folates, genetic MTR knockout in tumour cells leads to folate trapping, purine synthesis stalling, nucleotide depletion and impaired growth in cell culture and as xenografts. These defects are rescued by free folate but not one-carbon unit supplementation. Thus, MTR plays a crucial role in liberating THF for use in one-carbon metabolism.
    DOI:  https://doi.org/10.1038/s42255-021-00465-w
  7. Nat Metab. 2021 Nov;3(11): 1521-1535
    The metabolic growth limitations of petite cells lacking the mitochondrial genome.
    Jakob Vowinckel, Johannes Hartl, Hans Marx, Martin Kerick, Kathrin Runggatscher, Markus A Keller, Michael Mülleder, Jason Day, Manuela Weber, Mark Rinnerthaler, Jason S L Yu, Simran Kaur Aulakh, Andrea Lehmann, Diethard Mattanovich, Bernd Timmermann, Nianshu Zhang, Cory D Dunn, James I MacRae, Michael Breitenbach, Markus Ralser.
      Eukaryotic cells can survive the loss of their mitochondrial genome, but consequently suffer from severe growth defects. 'Petite yeasts', characterized by mitochondrial genome loss, are instrumental for studying mitochondrial function and physiology. However, the molecular cause of their reduced growth rate remains an open question. Here we show that petite cells suffer from an insufficient capacity to synthesize glutamate, glutamine, leucine and arginine, negatively impacting their growth. Using a combination of molecular genetics and omics approaches, we demonstrate the evolution of fast growth overcomes these amino acid deficiencies, by alleviating a perturbation in mitochondrial iron metabolism and by restoring a defect in the mitochondrial tricarboxylic acid cycle, caused by aconitase inhibition. Our results hence explain the slow growth of mitochondrial genome-deficient cells with a partial auxotrophy in four amino acids that results from distorted iron metabolism and an inhibited tricarboxylic acid cycle.
    DOI:  https://doi.org/10.1038/s42255-021-00477-6
  8. Autophagy. 2021 Nov 15. 1-3
    Beyond mitophagy: mitochondrial-derived vesicles can get the job done!
    Payel Mondal, Christina Towers.
      Mitochondria are critical organelles that maintain cellular metabolism and overall function. The catabolic pathway of autophagy plays a central role in recycling damaged mitochondria. Although the autophagy pathway is indispensable for some cancer cell survival, our latest study shows that rare autophagy-dependent cancer cells can adapt to loss of this core pathway. In the process, the autophagy-deficient cells acquire unique dependencies on alternate forms of mitochondrial homeostasis. These rare autophagy-deficient clones circumvent the lack of canonical autophagy by increasing mitochondrial dynamics and by recycling damaged mitochondria via mitochondrial-derived vesicles (MDVs). These studies are the first to implicate MDVs in cancer cell metabolism although many unanswered questions remain about this non-canonical pathway.
    Keywords:  Cancer; mitochondrial fusion; mitochondrial-derived vesicles; mitophagy; non-canonical autophagy
    DOI:  https://doi.org/10.1080/15548627.2021.1999562
  9. Front Pharmacol. 2021 ;12 729367
    ROS/JNK/C-Jun Pathway is Involved in Chaetocin Induced Colorectal Cancer Cells Apoptosis and Macrophage Phagocytosis Enhancement.
    Huihui Wang, Chuangyu Wen, Siyu Chen, Weiqian Li, Qiyuan Qin, Lu He, Fang Wang, Junxiong Chen, Weibiao Ye, Wende Li, Junsheng Peng, Xiangling Yang, Huanliang Liu.
      There is an urgent need for novel agents for colorectal cancer (CRC) due to the increasing number of cases and drug-resistance related to current treatments. In this study, we aim to uncover the potential of chaetocin, a natural product, as a chemotherapeutic for CRC treatment. We showed that, regardless of 5-FU-resistance, chaetocin induced proliferation inhibition by causing G2/M phase arrest and caspase-dependent apoptosis in CRC cells. Mechanically, our results indicated that chaetocin could induce reactive oxygen species (ROS) accumulation and activate c-Jun N-terminal kinase (JNK)/c-Jun pathway in CRC cells. This was confirmed by which the JNK inhibitor SP600125 partially rescued CRC cells from chaetocin induced apoptosis and the ROS scavenger N-acetyl-L-cysteine (NAC) reversed both the chaetocin induced apoptosis and the JNK/c-Jun pathway activation. Additionally, this study indicated that chaetocin could down-regulate the expression of CD47 at both mRNA and protein levels, and enhance macrophages phagocytosis of CRC cells. Chaetocin also inhibited tumor growth in CRC xenograft models. In all, our study reveals that chaetocin induces CRC cell apoptosis, irrelevant to 5-FU sensitivity, by causing ROS accumulation and activating JNK/c-Jun, and enhances macrophages phagocytosis, which suggests chaetocin as a candidate for CRC chemotherapy.
    Keywords:  CD47; JNK/c-Jun pathway; ROS; apoptosis; chaetocin; colorectal cancer
    DOI:  https://doi.org/10.3389/fphar.2021.729367
  10. Nature. 2021 Nov 18.
    CRISPR screens unveil signal hubs for nutrient licensing of T cell immunity.
    Lingyun Long, Jun Wei, Seon Ah Lim, Jana L Raynor, Hao Shi, Jon P Connelly, Hong Wang, Cliff Guy, Boer Xie, Nicole M Chapman, Guotong Fu, Yanyan Wang, Hongling Huang, Wei Su, Jordy Saravia, Isabel Risch, Yong-Dong Wang, Yuxin Li, Mingming Niu, Yogesh Dhungana, Anil Kc, Peipei Zhou, Peter Vogel, Jiyang Yu, Shondra M Pruett-Miller, Junmin Peng, Hongbo Chi.
      Nutrients are emerging regulators of adaptive immunity1. Selective nutrients interplay with immunological signals to activate mechanistic target of rapamycin complex 1 (mTORC1), a key driver of cell metabolism2-4, but how these environmental signals are integrated for immune regulation remains unclear. Here we use genome-wide CRISPR screening combined with protein-protein interaction networks to identify regulatory modules that mediate immune receptor- and nutrient-dependent signalling to mTORC1 in mouse regulatory T (Treg) cells. SEC31A is identified to promote mTORC1 activation by interacting with the GATOR2 component SEC13 to protect it from SKP1-dependent proteasomal degradation. Accordingly, loss of SEC31A impairs T cell priming and Treg suppressive function in mice. In addition, the SWI/SNF complex restricts expression of the amino acid sensor CASTOR1, thereby enhancing mTORC1 activation. Moreover, we reveal that the CCDC101-associated SAGA complex is a potent inhibitor of mTORC1, which limits the expression of glucose and amino acid transporters and maintains T cell quiescence in vivo. Specific deletion of Ccdc101 in mouse Treg cells results in uncontrolled inflammation but improved antitumour immunity. Collectively, our results establish epigenetic and post-translational mechanisms that underpin how nutrient transporters, sensors and transducers interplay with immune signals for three-tiered regulation of mTORC1 activity and identify their pivotal roles in licensing T cell immunity and immune tolerance.
    DOI:  https://doi.org/10.1038/s41586-021-04109-7
  11. Sci Rep. 2021 Nov 18. 11(1): 22486
    Metabolic characterization and metabolism-score of tumor to predict the prognosis in prostate cancer.
    Yanlong Zhang, Xuezhi Liang, Liyun Zhang, Dongwen Wang.
      Tumor metabolism patterns have been reported to be associated with the prognosis of many cancers. However, the metabolic mechanisms underlying prostate cancer (PCa) remain unknown. This study aimed to explore the metabolic characteristics of PCa. First, we downloaded mRNA expression data and clinical information of PCa samples from multiple databases and quantified the metabolic pathway activity level using single-sample gene set enrichment analysis (ssGSEA). Through unsupervised clustering and principal component analyses, we explored metabolic characteristics and constructed a metabolic score for PCa. Then, we independently validated the prognostic value of our metabolic score and the nomogram based on the metabolic score in multiple databases. Next, we found the metabolic score to be closely related to the tumor microenvironment and DNA mutation using multi-omics data and ssGSEA. Finally, we found different features of drug sensitivity in PCa patients in the high/low metabolic score groups. In total, 1232 samples were analyzed in the present study. Overall, an improved understanding of tumor metabolism through the characterization of metabolic clusters and metabolic score may help clinicians predict prognosis and aid the development of more personalized anti-tumor therapeutic strategies for PCa.
    DOI:  https://doi.org/10.1038/s41598-021-01140-6
  12. Mol Nutr Food Res. 2021 Nov 17. e2100728
    Cysteine exerts an essential role in maintaining intestinal integrity and function independent of glutathione.
    Ning Jiao, Lu Wang, Yubo Wang, Doudou Xu, Xin Zhang, Jingdong Yin.
       SCOPE: Enteral feeding is a primary source of cysteine for intestinal mucosa given negligible transsulfuration activity in enterocytes and furthermore very few cysteine uptake from arterial blood. This study aims to explore the role of cysteine in maintaining intestinal integrity and function.
    METHODS AND RESULTS: The intestinal porcine enterocytes (IPEC-J2) were cultured in a cysteine-deprived medium with or without glutathione supplementation upon the inhibitions of glutathione synthesis or degradation. As a result, cysteine deprivation impaired mitochondrial function, suppressed mechanistic target of rapamycin (mTOR) signaling and activated general control nonderepressible 2 (GCN2) signaling, and might lead to resultant ferroptosis. Glutathione supplementation could restore the impairment through degradating into cysteine, while glutathione synthesis inhibition did not disturb the role of cysteine in keeping the intestinal epithelial cells. Furthermore, piglets were fed with cysteine-deficient, -adequate and -surplus diet for 28 d as a porcine model. We evidenced that intestinal integrity and individual growth benefit from adequate dietary cysteine.
    CONCLUSION: Adequate dietary cysteine supply is essential for intestinal mucosal integrity, epithelial cell turnover and amino acid sensing as well as optimal individual growth. Cysteine exerts its role independent of glutathione and glutathione restores the impairment of cysteine-deprivation on intestinal mucosal through degrading into cysteine. This article is protected by copyright. All rights reserved.
    Keywords:  Cysteine; Glutathione; Growth; Intestinal epithelial cell; Pigs
    DOI:  https://doi.org/10.1002/mnfr.202100728
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