bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2022‒07‒24
fourteen papers selected by
Sreeparna Banerjee
Middle East Technical University
  1. Glutamine addiction promotes glucose oxidation in triple-negative breast cancer.
  2. Extrinsic hyaluronic acid induction differentially modulates intracellular glutamine metabolism in breast cancer stem cells.
  3. Activated amino acid response pathway generates apatinib resistance by reprograming glutamine metabolism in non-small-cell lung cancer.
  4. Glutamine Availability Regulates the Development of Aging Mediated by mTOR Signaling and Autophagy.
  5. Sirtuin 4 Inhibits Prostate Cancer Progression and Metastasis by Modulating p21 Nuclear Translocation and Glutamate Dehydrogenase 1 ADP-Ribosylation.
  6. Moving towards a novel therapeutic strategy for hyperammonemia that targets glutamine metabolism.
  7. Glutamine deficiency promotes recurrence and metastasis in colorectal cancer through enhancing epithelial-mesenchymal transition.
  8. Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR-Driven Lung Cancer.
  9. SIRT4 functions as a tumor suppressor during prostate cancer by inducing apoptosis and inhibiting glutamine metabolism.
  10. Hypoxia-Mediated ATF4 Induction Promotes Survival in Detached Conditions in Metastatic Murine Mammary Cancer Cells.
  11. Cell Metabolomics Study on Synergistic anti-Hepatocellular Carcinoma Effect of Aidi Injection Combined with Doxorubicin.
  12. Interplay between Cellular Metabolism and DNA viruses.
  13. Deacetylation of Glutaminase by HDAC4 contributes to Lung Cancer Tumorigenesis.
  14. Activating mTOR mutations are detrimental in nutrient-poor conditions.
  1. Oncogene. 2022 Jul 18.
    Glutamine addiction promotes glucose oxidation in triple-negative breast cancer.
    Lake-Ee Quek, Michelle van Geldermalsen, Yi Fang Guan, Kanu Wahi, Chelsea Mayoh, Seher Balaban, Angel Pang, Qian Wang, Mark J Cowley, Kristin K Brown, Nigel Turner, Andrew J Hoy, Jeff Holst.
      Glutamine is a conditionally essential nutrient for many cancer cells, but it remains unclear how consuming glutamine in excess of growth requirements confers greater fitness to glutamine-addicted cancers. By contrasting two breast cancer subtypes with distinct glutamine dependencies, we show that glutamine-indispensable triple-negative breast cancer (TNBC) cells rely on a non-canonical glutamine-to-glutamate overflow, with glutamine carbon routed once through the TCA cycle. Importantly, this single-pass glutaminolysis increases TCA cycle fluxes and replenishes TCA cycle intermediates in TNBC cells, a process that achieves net oxidation of glucose but not glutamine. The coupling of glucose and glutamine catabolism appears hard-wired via a distinct TNBC gene expression profile biased to strip and then sequester glutamine nitrogen, but hampers the ability of TNBC cells to oxidise glucose when glutamine is limiting. Our results provide a new understanding of how metabolically rigid TNBC cells are sensitive to glutamine deprivation and a way to select vulnerable TNBC subtypes that may be responsive to metabolic-targeted therapies.
    DOI:  https://doi.org/10.1038/s41388-022-02408-5
  2. Int J Biol Macromol. 2022 Jul 18. pii: S0141-8130(22)01532-X. [Epub ahead of print]
    Extrinsic hyaluronic acid induction differentially modulates intracellular glutamine metabolism in breast cancer stem cells.
    Heena Jariyal, Harsh Thakkar, Adarsh Suresh Kumar, Ravi Shah, Akshay Srivastava.
      The effect of low and high molecular weight hyaluronic acid on glutamine metabolism in luminal and basal breast cancer and cancer stem cells is being investigated. In luminal cell lines (MCF-7), HA enhances the intracellular utilization of gln in redox metabolism and decreases its use in TCA. On the contrary, in MDAMB-231 cells, HA induces the uptake of gln to be utilized in anaplerosis rather than ROS maintenance. However, in MCF-7 CSCs, HA induces up-regulation of xCT, further, it uses gln-derived glutamate for the exchange of cystine, thus maintaining ROS levels through xCT. MDA-MB-231 CSCs reduce the secretion of glutamate in response to HA and decrease the gln flux towards reductive carboxylation. Conclusively, our study demonstrated that although the uptake of gln is enhanced by HA, it is differentially utilized intracellularly in breast cancer cells. This study could significantly influence the therapeutics involving HA and Gln in breast cancer.
    Keywords:  Alanine-serine-cysteine transporter; Breast cancer stem cells; Cystine–glutamate exchanger transporter; Glutamine; Hyaluronic acid; Reductive carboxylation
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.07.099
  3. Cell Death Dis. 2022 Jul 21. 13(7): 636
    Activated amino acid response pathway generates apatinib resistance by reprograming glutamine metabolism in non-small-cell lung cancer.
    Xiaoshu Zhou, Rui Zhou, Xinrui Rao, Jiaxin Hong, Qianwen Li, Xiaohua Jie, Jian Wang, Yingzhuo Xu, Kuikui Zhu, Zhenyu Li, Gang Wu.
      The efficacy of apatinib has been confirmed in the treatment of solid tumors, including non-small-cell lung cancer (NSCLC). However, the direct functional mechanisms of tumor lethality mediated by apatinib and the precise mechanisms of drug resistance are largely unknown. In this study, we demonstrated that apatinib could reprogram glutamine metabolism in human NSCLC via a mechanism involved in amino acid metabolic imbalances. Apatinib repressed the expression of GLS1, the initial and rate-limiting enzyme of glutamine catabolism. However, the broken metabolic balance led to the activation of the amino acid response (AAR) pathway, known as the GCN2/eIF2α/ATF4 pathway. Moreover, activation of ATF4 was responsible for the induction of SLC1A5 and ASNS, which promoted the consumption and metabolization of glutamine. Interestingly, the combination of apatinib and ATF4 silencing abolished glutamine metabolism in NSCLC cells. Moreover, knockdown of ATF4 enhanced the antitumor effect of apatinib both in vitro and in vivo. In summary, this study showed that apatinib could reprogram glutamine metabolism through the activation of the AAR pathway in human NSCLC cells and indicated that targeting ATF4 is a potential therapeutic strategy for relieving apatinib resistance.
    DOI:  https://doi.org/10.1038/s41419-022-05079-y
  4. Front Pharmacol. 2022 ;13 924081
    Glutamine Availability Regulates the Development of Aging Mediated by mTOR Signaling and Autophagy.
    Jiao Zhou, Honghan Chen, Jintao Du, Haoran Tai, Xiaojuan Han, Ning Huang, Xiaobo Wang, Hui Gong, Mingyao Yang, Hengyi Xiao.
      Glutamine is a conditionally essential amino acid involved in energy production and redox homeostasis. Aging is commonly characterized by energy generation reduction and redox homeostasis dysfunction. Various aging-related diseases have been reported to be accompanied by glutamine exhaustion. Glutamine supplementation has been used as a nutritional therapy for patients and the elderly, although the mechanism by which glutamine availability affects aging remains elusive. Here, we show that chronic glutamine deprivation induces senescence in fibroblasts and aging in Drosophila melanogaster, while glutamine supplementation protects against oxidative stress-induced cellular senescence and rescues the D-galactose-prompted progeria phenotype in mice. Intriguingly, we found that long-term glutamine deprivation activates the Akt-mTOR pathway, together with the suppression of autolysosome function. However, the inhibition of the Akt-mTOR pathway effectively rescued the autophagy impairment and cellular senescence caused by glutamine deprivation. Collectively, our study demonstrates a novel interplay between glutamine availability and the aging process. Mechanistically, long-term glutamine deprivation could evoke mammalian target of rapamycin (mTOR) pathway activation and autophagy impairment. These findings provide new insights into the connection between glutamine availability and the aging process.
    Keywords:  aging; autophagy; cellular senescence; glutamine; mTOR
    DOI:  https://doi.org/10.3389/fphar.2022.924081
  5. J Oncol. 2022 ;2022 5498743
    Sirtuin 4 Inhibits Prostate Cancer Progression and Metastasis by Modulating p21 Nuclear Translocation and Glutamate Dehydrogenase 1 ADP-Ribosylation.
    Liang Mao, Xi Hong, Luwei Xu, Xinning Wang, Jingyu Liu, Hao Wang, Yiguan Qian, Jun Zhao, Ruipeng Jia.
      Protein posttranslational modification regulates several biological mechanisms, including tumor progression. In this study, we show that the mitochondrial Sirtuin 4 (SIRT4), which has ADP-ribosylation activity, plays a role in prostate cancer (PCa) progression. Firstly, SIRT4 expression was verified in PCa tissues and cell lines by quantitative real-time PCR (qRT-PCR) and western blotting. Subsequently, we established stable PC-3 and 22rv1 cells that overexpressed SIRT4 and knocked down SIRT4, respectively. The functions of SIRT4 in PCa were explored through various phenotype experiments. The mechanism underlying the functions of SIRT4 was investigated through western blotting, immunoprecipitation, immunofluorescence, and nuclear and cytoplasmic extraction assays. We revealed that SIRT4 inhibited cell progression both in vivo and in vitro. Mechanistically, on the one hand, SIRT4 promoted the ADP-ribosylation of glutamate dehydrogenase 1 to inhibit the glutamine metabolism pathways. On the other hand, SIRT4 inhibited the phosphorylation of AKT, thereby affecting p21 phosphorylation and its cellular localization for cell cycle arrest. In conclusion, our study indicates that SIRT4 is directly associated with PCa progression and could be a novel target for PCa therapy.
    DOI:  https://doi.org/10.1155/2022/5498743
  6. J Inherit Metab Dis. 2022 Jul 22.
    Moving towards a novel therapeutic strategy for hyperammonemia that targets glutamine metabolism.
    Kaori Fukui, Tomoyuki Takahashi, Hitomi Matsunari, Ayuko Uchikura, Masahito Watanabe, Hiroshi Nagashima, Naotada Ishihara, Tatsuyuki Kakuma, Yoriko Watanabe, Yushiro Yamashita, Makoto Yoshino.
      Patients with urea cycle disorders intermittently develop episodes of decompensation with hyperammonemia. Although such an episode is often associated with starvation and catabolism, its molecular basis is not fully understood. First, we attempted to elucidate the mechanism of such starvation-associated hyperammonemia. Using a mouse embryonic fibroblast (MEF) culture system, we found that glucose starvation increases ammonia production, and that this increase is associated with enhanced glutaminolysis. These results led us to focus on α-ketoglutarate (AKG), a glutamate dehydrogenase inhibitor and a major anaplerotic metabolite. Hence, we sought to determine the effect of dimethyl α-ketoglutarate (DKG), a cell-permeable AKG analog, on MEFs and found that DKG mitigates ammonia production primarily by reducing flux through glutamate dehydrogenase. We also verified that DKG reduces ammonia in an NH4 Cl-challenged hyperammonemia mouse model and observed that DKG administration reduces plasma ammonia concentration to 22.8% of the mean value for control mice that received only NH4 Cl. In addition, we detected increases in ornithine concentration and in the ratio of ornithine to arginine following DKG treatment. We subsequently administered DKG intravenously to a newborn pig with hyperammonemia due to ornithine transcarbamylase deficiency and found that blood ammonia concentration declined significantly over time. We determined that this effect is associated with facilitated reductive amination and glutamine synthesis. Our present data indicate that energy starvation triggers hyperammonemia through enhanced glutaminolysis and that DKG reduces ammonia accumulation via pleiotropic mechanisms both in vitro and in vivo. Thus, cell-permeable forms of AKG are feasible candidates for a novel hyperammonemia treatment.
    Keywords:  anaplerosis; glutamate dehydrogenase; glutaminase; glutaminolysis; hyperammonemia; ornithine transcarbamylase deficiency; α-ketoglutarate
    DOI:  https://doi.org/10.1002/jimd.12540
  7. J Transl Med. 2022 Jul 22. 20(1): 330
    Glutamine deficiency promotes recurrence and metastasis in colorectal cancer through enhancing epithelial-mesenchymal transition.
    Hongyan Sun, Chuan Zhang, Yang Zheng, Chenlu Liu, Xue Wang, Xianling Cong.
      BACKGROUND: Glutamine is the most abundant amino acid in the body and plays a vital role in colorectal cancer (CRC) cell metabolism. However, limited studies have investigated the clinical and prognostic significance of preoperative serum glutamine levels in patients with colorectal cancer, and the underlying mechanism has not been explored.METHODS: A total of 121 newly diagnosed CRC patients between 2012 and 2016 were enrolled in this study. Serum glutamine levels were detected, and their associations with clinicopathological characteristics, systemic inflammation markers, carcinoembryonic antigen (CEA) and prognosis were analysed. In addition, the effect of glutamine depletion on recurrence and metastasis was examined in SW480 and DLD1 human CRC cell lines, and epithelial-mesenchymal transition (EMT)-related markers were detected to reveal the possible mechanism.
    RESULTS: A decreased preoperative serum level of glutamine was associated with a higher T-class and lymph node metastasis (P < 0.05). A higher serum level of glutamine correlated with a lower CEA level (r = - 0.25, P = 0.02). Low glutamine levels were correlated with shorter overall survival (OS) and disease-free survival (DFS). Multivariate Cox regression analysis showed that serum glutamine was an independent prognostic factor for DFS (P = 0.018), and a nomogram predicting the probability of 1-, 3- and 5-year DFS after radical surgery was built. In addition, glutamine deficiency promoted the migration and invasion of CRC cells. E-cadherin, a vital marker of EMT, was decreased, and EMT transcription factors, including zeb1and zeb2, were upregulated in this process.
    CONCLUSIONS: This study elucidated that preoperative serum glutamine is an independent prognostic biomarker to predict CRC progression and suggested that glutamine deprivation might promote migration and invasion in CRC cells by inducing the EMT process.
    DOI:  https://doi.org/10.1186/s12967-022-03523-3
  8. Adv Sci (Weinh). 2022 Jul 21. e2105885
    Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR-Driven Lung Cancer.
    Mofei Huang, Donghai Xiong, Jing Pan, Qi Zhang, Shizuko Sei, Robert H Shoemaker, Ronald A Lubet, Luis M Montuenga, Yian Wang, Barbara S Slusher, Ming You.
      Lung cancer is the leading cause of cancer death worldwide. Vaccination against EGFR can be one of the venues to prevent lung cancer. Blocking glutamine metabolism has been shown to improve anticancer immunity. Here, the authors report that JHU083, an orally active glutamine antagonist prodrug designed to be preferentially activated in the tumor microenvironment, has potent anticancer effects on EGFR-driven mouse lung tumorigenesis. Lung tumor development is significantly suppressed when treatment with JHU083 is combined with an EGFR peptide vaccine (EVax) than either single treatment. Flow cytometry and single-cell RNA sequencing of the lung tumors reveal that JHU083 increases CD8+ T cell and CD4+ Th1 cell infiltration, while EVax elicits robust Th1 cell-mediated immune responses and protects mice against EGFRL858R mutation-driven lung tumorigenesis. JHU083 treatment decreases immune suppressive cells, including both monocytic- and granulocytic-myeloid-derived suppressor cells, regulatory T cells, and pro-tumor CD4+ Th17 cells in mouse models. Interestingly, Th1 cells are found to robustly upregulate oxidative metabolism and adopt a highly activated and memory-like phenotype upon glutamine inhibition. These results suggest that JHU083 is highly effective against EGFR-driven lung tumorigenesis and promotes an adaptive T cell-mediated tumor-specific immune response that enhances the efficacy of EVax.
    Keywords:  JHU-083; epidermal growth factor receptor vaccines; glutamine metabolism; lung tumorigenesis; tumor immune microenvironment
    DOI:  https://doi.org/10.1002/advs.202105885
  9. Sci Rep. 2022 Jul 16. 12(1): 12208
    SIRT4 functions as a tumor suppressor during prostate cancer by inducing apoptosis and inhibiting glutamine metabolism.
    Guohao Cai, Zhuhui Ge, Yunqiu Xu, Liangliang Cai, Pingliang Sun, Guoyu Huang.
      Localized in the mitochondria, SIRT4 is a nicotinamide adenine dinucleotide (NAD +) -dependent adenosine diphosphate (ADP) -ribosyltransferase and is one of the least characterized members of the sirtuin family. Although it is well known that it shows deacetylase activity for energy metabolism, little is understood about its function in tumorigenesis. Recent research suggests that SIRT4 may work as both a tumor suppressor gene and an oncogene. However, the clinical significance of SIRT4 in prostate cancer remains unknown. In this study, we evaluated SIRT4 protein levels in cancerous prostate tissue and corresponding non-tumor prostate tissue via immunohistochemical staining on a tissue microarray including tissues from 89 prostate cancer patients. The association between SIRT4 expression and Gleason score was also determined. Further, shSIRT4 or stable prostate cancer cell lines (22RV1) overexpressing SIRT4 were constructed via lentiviral infection. Using Cell-Counting Kit-8 (CCK-8) assay, wound healing assay, migration, and invasion and apoptosis assays, the effects of SIRT4 on the migration, invasion ability, and proliferation of prostate cancer cells were investigated. We also determined the effect of SIRT4 on glutamine metabolism in 22RV1 cells. We found the protein levels of SIRT4 in prostate cancer tissues were significantly lower than those in their non-neoplastic tissue counterparts (P < 0.01); a lower SIRT4 level was also significantly associated with a higher Gleason score (P < 0.01). SIRT4 suppressed the migration, invasion capabilities, and proliferation of prostate cancer cells and induced cellular apoptosis. Furthermore, the invasion and migration of 22RV1 cells were mechanistically inhibited by SIRT4 via glutamine metabolism inhibition. In conclusion, the present study's findings showed that SIRT4 protein levels are significantly associated with the Gleason score in patients with prostate cancer, and SIRT4 exerts a tumor-suppressive effect on prostate cancer cells by inhibiting glutamine metabolism. Thus, SIRT4 may serve as a potential novel therapeutic target for prostate cancer.
    DOI:  https://doi.org/10.1038/s41598-022-16610-8
  10. Front Oncol. 2022 ;12 767479
    Hypoxia-Mediated ATF4 Induction Promotes Survival in Detached Conditions in Metastatic Murine Mammary Cancer Cells.
    Violet A Kiesel, Madeline P Sheeley, Emily M Hicks, Chaylen Andolino, Shawn S Donkin, Michael K Wendt, Stephen D Hursting, Dorothy Teegarden.
      Regions of hypoxia are common in solid tumors and drive changes in gene expression that increase risk of cancer metastasis. Tumor cells must respond to the stress of hypoxia by activating genes to modify cell metabolism and antioxidant response to improve survival. The goal of the current study was to determine the effect of hypoxia on cell metabolism and markers of oxidative stress in metastatic (metM-Wntlung) compared with nonmetastatic (M-Wnt) murine mammary cancer cell lines. We show that hypoxia induced a greater suppression of glutamine to glutamate conversion in metastatic cells (13% in metastatic cells compared to 7% in nonmetastatic cells). We also show that hypoxia increased expression of genes involved in antioxidant response in metastatic compared to nonmetastatic cells, including glutamate cysteine ligase catalytic and modifier subunits and malic enzyme 1. Interestingly, hypoxia increased the mRNA level of the transaminase glutamic pyruvic transaminase 2 (Gpt2, 7.7-fold) only in metM-Wntlung cells. The change in Gpt2 expression was accompanied by transcriptional (4.2-fold) and translational (6.5-fold) induction of the integrated stress response effector protein activating transcription factor 4 (ATF4). Genetic depletion ATF4 demonstrated importance of this molecule for survival of hypoxic metastatic cells in detached conditions. These findings indicate that more aggressive, metastatic cancer cells utilize hypoxia for metabolic reprogramming and induction of antioxidant defense, including activation of ATF4, for survival in detached conditions.
    Keywords:  ATF4 activating transcription factor 4; breast cancer; cell stress; hypoxia; integrated stress response (ISR); metastasis
    DOI:  https://doi.org/10.3389/fonc.2022.767479
  11. Biomed Chromatogr. 2022 Jul 18. e5451
    Cell Metabolomics Study on Synergistic anti-Hepatocellular Carcinoma Effect of Aidi Injection Combined with Doxorubicin.
    Yanli Wang, Xiaoqing Zhu, Kailiang Wang, Ying Cai, Chunhua Liu, Jie Pan, Jia Sun, Ting Liu, Yong Huang, Yongjun Li, Yuan Lu.
      Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the second most common cause of cancer deaths. This study aimed to explore the inhibitory effect and mechanism of Aidi injection (ADI) combined with doxorubicin (DOX) in HCC treatment. The drug concentrations in combined threapy was determined by investigating the effect of various concentrations of ADI and DOX on the viability of H22 cells. The combination index (CI) was also calculated. A metabolomic strategy based on ultrahigh performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) platform was established to analyze the metabolites. As a result, the CI values were less than 1, indicating that the combination of ADI and DOX exerted a synergistic effect on HCC treatment. The combination of 40‰ ADI and 1 μmol/L DOX had the strongest inhibitory effect and was used for subsequent metabolomic analysis. A total of 19 metabolic markers were obtained in metabolomic analysis, including amino acids (L-glutamic acid, L-arginine, and L-tyrosine), organic acids (succinic acid and citric acid), adenosine, and hypoxanthine , etc. Compared with the treatment using DOX or ADI alone, the combined therapy further regulated the levels of metabolic markers in HCC, which may be the reason for the synergistic effect. Seven metabolic pathways were significantly enriched, including phenylalanine, tyrosine and tryptophan biosynthesis, D-glutamine and D-glutamate metabolism, alanine, aspartate and glutamate metabolism, phenylalanine metabolism, arginine biosynthesis, tricarboxylic acid (TCA) cycle, and purine metabolism. These findings demonstrated that ADI combined with DOX can effectively inhibit the viability of H22 cells, which may exert a synergistic anti-tumor effect by balancing the metabolism of amino acids and energy-related substances.
    Keywords:  Aidi injection; Cell metabolomics; Doxorubicin; H22 hepatocellular carcinoma; Synergistic effect
    DOI:  https://doi.org/10.1002/bmc.5451
  12. J Med Virol. 2022 Jul 22.
    Interplay between Cellular Metabolism and DNA viruses.
    Milad Zandi, Somayeh Shokri, Shahab Mahmoudvand, Ahmad Hosseinzadeh Adli, Ramin Mohammadi, Azita Haddadi.
      Viruses as intracellular pathogens hijack the host metabolism and reprogram to facilitate optimal virus production. DNA viruses can cause alterations in several metabolic pathways, including aerobic glycolysis also known as the Warburg effect, pentose phosphate pathway (PPP) activation, and amino acid catabolism such as glutaminolysis, nucleotide biosynthesis, lipid metabolism, and amino acid biosynthesis. The available energy for productive infection can be increased in infected cells via modification of different carbon source utilization. This review discusses the metabolic alterations of the DNA viruses that will be the basis for future novel therapeutic approaches. This article is protected by copyright. All rights reserved.
    Keywords:  glutaminolysis; glycolysis; host metabolism; lipid metabolism; viruses
    DOI:  https://doi.org/10.1002/jmv.28018
  13. Int J Biol Sci. 2022 ;18(11): 4452-4465
    Deacetylation of Glutaminase by HDAC4 contributes to Lung Cancer Tumorigenesis.
    Tao Wang, Zhuo Lu, Tianyu Han, Yanan Wang, Mingxi Gan, Jian-Bin Wang.
      Inhibiting cancer metabolism via glutaminase (GAC) is a promising strategy to disrupt tumor progression. However, mechanism regarding GAC acetylation remains mostly unknown. In this study, we demonstrate that lysine acetylation is a vital post-translational modification that inhibits GAC activity in non-small cell lung cancer (NSCLC). We identify that Lys311 is the key acetylation site on GAC, which is deacetylated by HDAC4, a class II deacetylase. Lys311 acetylation stimulates the interaction between GAC and TRIM21, an E3 ubiquitin ligase of the tripartite motif (TRIM) family, therefore promoting GAC K63-linked ubiquitination and inhibiting GAC activity. Furthermore, GACK311Q mutation in A549 cells decreases cell proliferation and alleviates tumor malignancy. Our findings reveal a novel mechanism of GAC regulation by acetylation and ubiquitination that participates in non-small cell lung cancer tumorigenesis.
    Keywords:  HDAC4; TRIM21; acetylation; glutaminase; non-small cell lung cancer
    DOI:  https://doi.org/10.7150/ijbs.69882
  14. Cancer Res. 2022 Jul 22. pii: CAN-22-0121. [Epub ahead of print]
    Activating mTOR mutations are detrimental in nutrient-poor conditions.
    Agata A Bielska, Caitlin F Harrigan, Yeon Ju Kyung, Quaid Morris, Wilhelm Palm, Craig B Thompson.
      The mechanistic target of rapamycin (mTOR) is a key regulator of cell growth that integrates growth factor signaling and nutrient availability and is a downstream effector of oncogenic receptor tyrosine kinases (RTKs) and PI3K/Akt signaling. Thus, activating mTOR mutations would be expected to enhance growth in many tumor types. However, tumor sequencing data has shown that mTOR mutations are enriched only in renal clear cell carcinoma, a clinically hypervascular tumor unlikely to be constrained by nutrient availability. To further define this cancer type-specific restriction, we studied activating mutations in mTOR. All mTOR mutants tested enhanced growth in a cell type agnostic manner under nutrient-replete conditions but were detrimental to cell survival in nutrient-poor conditions. Consistently, analysis of tumor data demonstrated that oncogenic mutations in the nutrient-sensing arm of the mTOR pathway display a similar phenotype and were exceedingly rare in human cancers of all types. Together, these data suggest that maintaining the ability to turn off mTOR signaling in response to changing nutrient availability is retained in most naturally occurring tumors.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-0121
This page is being maintained by Thomas Krichel. It was last updated on 2022‒07‒26 at 13:18:45.