bims-glucam 2021-02-21 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2021–02–21
nine papers selected by
Sreeparna Banerjee, Middle East Technical University

Selective glutamine metabolism inhibition in tumor cells improves antitumor T lymphocyte activity in triple-negative breast cancer.
Reprogramming of glutamine metabolism via glutamine synthetase silencing induces cisplatin resistance in A2780 ovarian cancer cells.
SARS-CoV-2 and Glutamine: SARS-CoV-2 Triggered Pathogenesis via Metabolic Reprograming of Glutamine in Host Cells.
Glutamine Deprivation Promotes the Generation and Mobilization of MDSCs by Enhancing Expression of G-CSF and GM-CSF.
Neural signaling modulates metabolism of gastric cancer.
Role of Glutamine in the Management of Oral Mucositis in Patients with Cancer: A Meta-Analysis of Randomized Controlled Trials.
Selective killing of cancer cells harboring mutant RAS by concomitant inhibition of NADPH oxidase and glutathione biosynthesis.
STK1/LKB1 Mutations in NSCLC Are Associated with KEAP1/NRF2-Dependent Radiotherapy Resistance Targetable by Glutaminase Inhibition.
GABARAP suppresses EMT and breast cancer progression via the AKT/mTOR signaling pathway.

J Clin Invest. 2021 Feb 15. pii: 140100. [Epub ahead of print]131(4):

Selective glutamine metabolism inhibition in tumor cells improves antitumor T lymphocyte activity in triple-negative breast cancer.

Deanna N Edwards, Verra M Ngwa, Ariel L Raybuck, Shan Wang, Yoonha Hwang, Laura C Kim, Sung Hoon Cho, Yeeun Paik, Qingfei Wang, Siyuan Zhang, H Charles Manning, Jeffrey C Rathmell, Rebecca S Cook, Mark R Boothby, Jin Chen.

  Rapidly proliferating tumor and immune cells need metabolic programs that support energy and biomass production. The amino acid glutamine is consumed by effector T cells and glutamine-addicted triple-negative breast cancer (TNBC) cells, suggesting that a metabolic competition for glutamine may exist within the tumor microenvironment, potentially serving as a therapeutic intervention strategy. Here, we report that there is an inverse correlation between glutamine metabolic genes and markers of T cell-mediated cytotoxicity in human basal-like breast cancer (BLBC) patient data sets, with increased glutamine metabolism and decreased T cell cytotoxicity associated with poor survival. We found that tumor cell-specific loss of glutaminase (GLS), a key enzyme for glutamine metabolism, improved antitumor T cell activation in both a spontaneous mouse TNBC model and orthotopic grafts. The glutamine transporter inhibitor V-9302 selectively blocked glutamine uptake by TNBC cells but not CD8+ T cells, driving synthesis of glutathione, a major cellular antioxidant, to improve CD8+ T cell effector function. We propose a "glutamine steal" scenario, in which cancer cells deprive tumor-infiltrating lymphocytes of needed glutamine, thus impairing antitumor immune responses. Therefore, tumor-selective targeting of glutamine metabolism may be a promising therapeutic strategy in TNBC.

Keywords:  Amino acid metabolism; Breast cancer; Cancer immunotherapy; Oncology

DOI:  https://doi.org/10.1172/JCI140100
BMC Cancer. 2021 Feb 17. 21(1): 174

Reprogramming of glutamine metabolism via glutamine synthetase silencing induces cisplatin resistance in A2780 ovarian cancer cells.

Jing Guo, Kiyotoshi Satoh, Sho Tabata, Masaru Mori, Masaru Tomita, Tomoyoshi Soga.

   BACKGROUND: Cisplatin (CDDP) significantly prolongs survival in various cancers, but many patients also develop resistance that results in treatment failure. Thus, this study aimed to elucidate the underlying mechanisms by which ovarian cancer cells acquire CDDP resistance.
METHODS: We evaluated the metabolic profiles in CDDP-sensitive ovarian cancer A2780 cells and CDDP-resistant A2780cis cells using capillary electrophoresis-time-of-flight mass spectrometry (CE-TOFMS). We further examined the expression of glutamine metabolism enzymes using real-time PCR and Western blot analyses. Cell viability was accessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.
RESULTS: The results showed that levels of glutamine, glutamate, and glutathione (GSH), a key drug resistance mediator synthesized from glutamate, were significantly elevated in A2780cis cells than those in A2780 cells. Furthermore, glutamine starvation decreased the GSH levels and CDDP resistance in A2780cis cells. Interestingly, the expression of glutamine synthetase (GS/GLUL), which synthesizes glutamine from glutamate and thereby negatively regulates GSH production, was almost completely suppressed in resistant A2780cis cells. In addition, treatment of A2780cis cells with 5-aza-2'-deoxycytidine, a DNA-demethylating agent, restored GS expression and reduced CDDP resistance. In contrast, GS knockdown in CDDP-sensitive A2780 cells induced CDDP resistance.
CONCLUSIONS: The results indicate that upregulation of GSH synthesis from glutamine via DNA methylation-mediated silencing of GS causes CDDP resistance in A2780cis cells. Therefore, glutamine metabolism could be a novel therapeutic target against CDDP resistance.

Keywords:  CE-TOFMS; Cisplatin resistance; Glutamine synthetase; Metabolome; Ovarian cancer

DOI:  https://doi.org/10.1186/s12885-021-07879-5
Front Mol Biosci. 2020 ;7 627842

SARS-CoV-2 and Glutamine: SARS-CoV-2 Triggered Pathogenesis via Metabolic Reprograming of Glutamine in Host Cells.

Shiv Bharadwaj, Mahendra Singh, Nikhil Kirtipal, Sang Gu Kang.

  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as coronavirus disease 2019 (COVID-19) pandemic, has killed more than a million people worldwide, and researchers are constantly working to develop therapeutics in the treatment and prevention of this new viral infection. To infect and induced pathogenesis as observed in other viral infections, we postulated that SARS-CoV-2 may also require an escalation in the anabolic metabolism, such as glucose and glutamine, to support its energy and biosynthetic requirements during the infection cycle. Recently, the requirement of altered glucose metabolism in SARS-CoV-2 pathogenesis was demonstrated, but the role of dysregulated glutamine metabolism is not yet mentioned for its infection. In this perspective, we have attempted to provide a summary of possible biochemical events on putative metabolic reprograming of glutamine in host cells upon SARS-CoV-2 infection by comparison to other viral infections/cancer metabolism and available clinical data or research on SARS-CoV-2 pathogenesis. This systematic hypothesis concluded the vital role of glutaminase-1 (GLS1), phosphoserine aminotransferase (PSAT1), hypoxia-inducible factor-1 alpha (HIF-1α), mammalian target of rapamycin complex 1 (mTORC1), glutamine-fructose amidotransferase 1/2 (GFAT1/2), and transcription factor Myc as key cellular factors to mediate and promote the glutamine metabolic reprogramming in SARS-CoV-2 infected cells. In absence of concrete data available for SARS-CoV-2 induced metabolic reprogramming of glutamine, this study efforts to connect the gaps with available clinical shreds of evidence in SARS-CoV-2 infection with altered glutamine metabolism and hopefully could be beneficial in the designing of strategic methods for therapeutic development with elucidation using in vitro or in vivo approaches.

Keywords:  COVID-19; glutamine; glutaminolysis; hypoxia-inducible factor 1-alpha; metabolic reprogramming

DOI:  https://doi.org/10.3389/fmolb.2020.627842
Front Immunol. 2020 ;11 616367

Glutamine Deprivation Promotes the Generation and Mobilization of MDSCs by Enhancing Expression of G-CSF and GM-CSF.

Hong-Wei Sun, Wen-Chao Wu, Hai-Tian Chen, Yi-Tuo Xu, Yan-Yan Yang, Jing Chen, Xing-Juan Yu, Zilian Wang, Ze-Yu Shuang, Limin Zheng.

  Solid tumors are often challenged by hypoxic and nutrient-deprived tumor microenvironments (TME) as tumors progress, due to limited perfusion and rapid nutrient consumption. While cancer cells can demonstrate the ability to survive in nutrient-deprived conditions through multiple intrinsic alterations, it is poorly understood how nutrient-deprived cancer cells co-opt the TME to promote cancer cell survival and tumor progression. In the present study, we found that glutamine deprivation markedly potentiated the expression of G-CSF and GM-CSF in mouse mammary cancer cells. The IRE1α-JNK pathway, which is activated by glutamine starvation, was found to be important for the upregulation of these cytokines. G-CSF and GM-CSF are well-known facilitators of myelopoiesis and mobilization of hematopoietic progenitor cells (HPC). Consistently, as tumors progressed, we found that several myeloid HPC compartments were gradually decreased in the bone marrow but were significantly increased in the spleen. Mechanistically, the HPC-maintaining capacity of the bone marrow was significantly impaired in tumor-bearing mice, with lower expression of HPC maintaining genes (i.e., CXCL12, SCF, ANGPT1, and VCAM1), and reduced levels of mesenchymal stem cells and CXCL12-producing cells. Furthermore, the mobilized HPCs that displayed the capacity for myelopoiesis were also found to accumulate in tumor tissue. Tumor-infiltrating HPCs were highly proliferative and served as important sources of immunosuppressive myeloid-derived suppressor cells (MDSCs) in the TME. Our work has identified an important role for glutamine starvation in regulating the expression of G-CSF and GM-CSF, and in facilitating the generation of immunosuppressive MDSCs in breast cancer.

Keywords:  G-CSF; GM-CSF; MDSC; bone marrow; glutamine

DOI:  https://doi.org/10.3389/fimmu.2020.616367
iScience. 2021 Feb 19. 24(2): 102091

Neural signaling modulates metabolism of gastric cancer.

Hanne-Line Rabben, Gøran Troseth Andersen, Magnus Kringstad Olsen, Anders Øverby, Aleksandr Ianevski, Denis Kainov, Timothy Cragin Wang, Steinar Lundgren, Jon Erik Grønbech, Duan Chen, Chun-Mei Zhao.

  Tumors comprise cancer cells and the associated stromal and immune/inflammatory cells, i.e., tumor microenvironment (TME). Here, we identify a metabolic signature of human and mouse model of gastric cancer and show that vagotomy in the mouse model reverses the metabolic reprogramming, reflected by metabolic switch from glutaminolysis to OXPHOS/glycolysis and normalization of the energy metabolism in cancer cells and TME. We next identify and validate SNAP25, mTOR, PDP1/α-KGDH, and glutaminolysis as drug targets and accordingly propose a therapeutic strategy to target the nerve-cancer metabolism. We demonstrate the efficacy of nerve-cancer metabolism therapy by intratumoral injection of BoNT-A (SNAP25 inhibitor) with systemic administration of RAD001 and CPI-613 but not cytotoxic drugs on overall survival in mice and show the feasibility in patients. These findings point to the importance of neural signaling in modulating the tumor metabolism and provide a rational basis for clinical translation of the potential strategy for gastric cancer.

Keywords:  Cancer; Cancer Systems Biology

DOI:  https://doi.org/10.1016/j.isci.2021.102091
Nutr Cancer. 2021 Feb 19. 1-14

Role of Glutamine in the Management of Oral Mucositis in Patients with Cancer: A Meta-Analysis of Randomized Controlled Trials.

Gang Tang, Wang Huang, Linyu Zhang, Zhengqiang Wei.

As the effectiveness of glutamine supplementation for oral mucositis (OM) in patients with cancer remains controversial, a comprehensive summary and analysis of available evidence is necessary. The aim of the present meta-analysis was to evaluate the benefits of glutamine supplementation on OM and OM-related adverse reactions in patients with cancer receiving chemotherapy (CT) and/or radiotherapy (RT), using data from randomized controlled trials (RCTs). The PubMed, Embase, Cochrane Library, and Web of Science databases were searched for RCTs on the use of glutamine for treating OM, published until September 11, 2020. Risk ratios (RRs) or standardized mean differences (SMDs) and 95% confidence intervals (CI) were calculated using RevMan 5.3. Fifteen studies with 988 participants were included. Glutamine did not reduce the incidence of OM (RR 0.94), but it reduced the severity of OM (SMD -0.73) and incidence of severe OM (RR 0.41). Additionally, glutamine reduced the incidence of opioid analgesic use (RR 0.84), feeding tube use (RR 0.46), hospitalization (RR 0.39), and treatment interruption (RR 0.49) caused by OM. Glutamine effectively improved OM and reduced OM-related adverse reactions in patients with cancer receiving CT and/or RT.

DOI: https://doi.org/10.1080/01635581.2021.1889623
Cell Death Dis. 2021 Feb 16. 12(2): 189

Selective killing of cancer cells harboring mutant RAS by concomitant inhibition of NADPH oxidase and glutathione biosynthesis.

Muyun Liu, Dan Wang, Yongde Luo, Lianghao Hu, Yawei Bi, Juntao Ji, Haojie Huang, Guoqiang Wang, Liang Zhu, Jianjia Ma, Eunice Kim, Catherine K Luo, James L Abbruzzese, Xiaokun Li, Vincent W Yang, Zhaoshen Li, Weiqin Lu.

Oncogenic RAS is a critical driver for the initiation and progression of several types of cancers. However, effective therapeutic strategies by targeting RAS, in particular RASG12D and RASG12V, and associated downstream pathways have been so far unsuccessful. Treatment of oncogenic RAS-ravaged cancer patients remains a currently unmet clinical need. Consistent with a major role in cancer metabolism, oncogenic RAS activation elevates both reactive oxygen species (ROS)-generating NADPH oxidase (NOX) activity and ROS-scavenging glutathione biosynthesis. At a certain threshold, the heightened oxidative stress and antioxidant capability achieve a higher level of redox balance, on which cancer cells depend to gain a selective advantage on survival and proliferation. However, this prominent metabolic feature may irrevocably render cancer cells vulnerable to concurrent inhibition of both NOX activity and glutathione biosynthesis, which may be exploited as a novel therapeutic strategy. In this report, we test this hypothesis by treating the HRASG12V-transformed ovarian epithelial cells, mutant KRAS-harboring pancreatic and colon cancer cells of mouse and human origins, as well as cancer xenografts, with diphenyleneiodonium (DPI) and buthionine sulfoximine (BSO) combination, which inhibit NOX activity and glutathione biosynthesis, respectively. Our results demonstrate that concomitant targeting of NOX and glutathione biosynthesis induces a highly potent lethality to cancer cells harboring oncogenic RAS. Therefore, our studies provide a novel strategy against RAS-bearing cancers that warrants further mechanistic and translational investigation.

DOI: https://doi.org/10.1038/s41419-021-03473-6
Clin Cancer Res. 2020 Dec 15.

STK1/LKB1 Mutations in NSCLC Are Associated with KEAP1/NRF2-Dependent Radiotherapy Resistance Targetable by Glutaminase Inhibition.

Piyada Sitthideatphaiboon, Ana Galan-Cobo, Marcelo V Negrao, Xiao Qu, Alissa Poteete, Fahao Zhang, Diane D Liu, Whitney E Lewis, Haley N Kemp, Jeff Lewis, Waree Rinsurongkawong, Uma Giri, J Jack Lee, Jianjun Zhang, Jack A Roth, Stephen Swisher, John V Heymach.

PURPOSE: Radiotherapy with or without chemotherapy is a mainstay of treatment for locally advanced non-small cell lung cancer (NSCLC), but no predictive markers are currently available to select patients who will benefit from these therapies. In this study, we investigated the association between alterations in STK11/LKB1, the second most common tumor suppressor in NSCLC, and response to radiotherapy as well as potential therapeutic approaches to improve outcomes.
EXPERIMENTAL DESIGN: We conducted a retrospective analysis of 194 patients with stage I-III NSCLC, including 164 stage III patients bearing mutant or wild-type STK11/LKB1 treated with radiotherapy, and assessed locoregional recurrence (LRR), distant metastasis rates, disease-free survival (DFS), and overall survival (OS), and we investigated the causal role of LKB1 in mediating radiotherapy resistance using isogenic pairs of NSCLC cell lines with LKB1 loss or gain.
RESULTS: In stage III patients, with 4 years median follow-up, STK11/LKB1 mutations were associated with higher LRR (P = 0.0108), and shorter DFS (HR 2.530, P = 0.0029) and OS (HR 2.198, P = 0.0263). LKB1 loss promoted relative resistance to radiotherapy, which was dependent on the KEAP1/NRF2 pathway for redox homeostasis. Suppression of the KEAP1/NRF2 pathway via KEAP1 expression, or pharmacologic blockade of glutaminase (GLS) 1 sensitized LKB1-deficient tumors to radiotherapy.
CONCLUSIONS: These data provide evidence that LKB1 loss is associated with LRR and poor clinical outcomes in patients with NSCLC treated with radiotherapy and that targeting the KEAP1/NRF2 pathway or GLS inhibition are potential approaches to radiosensitize LKB1-deficient tumors.

DOI: https://doi.org/10.1158/1078-0432.CCR-20-2859
Aging (Albany NY). 2021 Feb 11. 13

GABARAP suppresses EMT and breast cancer progression via the AKT/mTOR signaling pathway.

Ying Liu, Dandan Wang, Mengxia Lei, Jiayi Gao, Yuqing Cui, Xiaoying Jin, Qiujie Yu, Ying Jiang, Yan Guo, Yali Liu, Li Cai, Xuesong Chen.

  Few studies have focused on γ-aminobutyric acid type A (GABAA) receptor-associated protein (GABARAP) in tumor progression. We investigated the expression and importance of GABARAP in breast cancer. We analyzed the expression of GABARAP and its relationship with clinicopathological features and prognosis (TCGA). To explain the role and potential mechanism of GABARAP in regulating tumor development, we performed acquisition and loss of function experiments using cell lines and models of mouse xenotransplantation. We found that GABARAP inhibited proliferation, migration and invasion in vitro and in vivo. Notably, low levels of GABARAP induced the epithelial-mesenchymal transition (EMT). Low levels of GABARAP increased p-AKT and p-mTOR levels, and a specific AKT pathway inhibitor reversed the downregulation of GABARAP-induced tumor progression. GABARAP negatively correlated with advanced clinicopathological features in clinical specimens, such as tumor size and TNM stage. Notably, patients with low GABARAP levels had a poor prognosis. Immunohistochemistry (IHC) revealed that GABARAP expression negatively correlated with matrix metalloproteinase (MMP) 2 and MMP14. Conclusively, these data indicate that GABARAP suppresses the malignant behaviors of breast cancer likely via the AKT/mTOR pathway. The targeting of GABARAP may improve the certainty of diagnosis and treatment strategies for breast cancer.

Keywords:  AKT/mTOR pathway; EMT; GABARAP; breast cancer; prognosis

DOI:  https://doi.org/10.18632/aging.202510