Compensatory glutamine metabolism promotes glioblastoma resistance to mTOR inhibitor treatment

Tanaka, Kazuhiro; Sasayama, Takashi; Irino, Yasuhiro; Takata, Kumi; Nagashima, Hiroaki; Satoh, Naoya; Kyotani, Katsusuke; Mizowaki, Takashi; Imahori, Taichiro; Endo, Yasuo; Masui, Kenta; Gini, Beatrice; Yang, Huijun; Hosoda, Kohkichi; Sasaki, Ryohei; Mischel, Paul S.; Kohmura, Eiji

doi:10.1172/jci78239

Cited by 202 publications

(172 citation statements)

References 42 publications

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“…mTOR inhibition Consistent with the role of glutamine in mTOR activation 219 and mTOR control of metabolism, GLS and mTOR inhibition are synthetic lethal 252 .…”

Section: Oncogenic Change Role In Glutamine Metabolismmentioning

confidence: 81%

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

Altman¹,

Stine²,

Dang³

2016

Nat Rev Cancer

235

136

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The resurgence of research in cancer metabolism has recently broadened interests beyond glucose and the Warburg Effect to other nutrients including glutamine. Because oncogenic alterations of metabolism render cancer cells addicted to nutrients, pathways involved in glycolysis or glutaminolysis could be exploited for therapeutic purposes. In this Review, we provide an updated overview of glutamine metabolism and its involvement in tumorigenesis in vitro and in vivo, and explore the recent potential applications of basic science discoveries in the clinical setting.

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“…mTOR inhibition Consistent with the role of glutamine in mTOR activation 219 and mTOR control of metabolism, GLS and mTOR inhibition are synthetic lethal 252 .…”

Section: Oncogenic Change Role In Glutamine Metabolismmentioning

confidence: 81%

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

Altman¹,

Stine²,

Dang³

2016

Nat Rev Cancer

235

136

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“…Through glutaminolysis, Gln replenishes the intracellular pool of Glu, which, through transaminases or Glu dehydrogenase, provides the anaplerotic Krebs cycle intermediate 2-OG. As shown in several human cancer models, 18,23,52,53 Gln-dependent anaplerosis is one of the mechanisms likely underlying Gln addiction, which implies the needing for large amounts of the amino acid. The anaplerotic role of Gln in MM cells and the Gln addiction of this cancer model are confirmed by the fall in 2-OG levels observed in Gln-depleted cells and by the rescue of Gln-depleted myeloma cells observed on medium supplementation with the membrane-permeant analog dimethyl-2-OG.…”

Section: Discussionmentioning

confidence: 99%

“…16 Gln is a substrate of several enzymes, playing an important role in various processes, such as the synthesis of nucleotides, other amino acids, or glucosamine. 17,18 Moreover, through the activity of glutaminases (GLS1 and GLS2), which hydrolyze the amide group obtaining NH 4 1 and Glu, Gln may fuel the intracellular pool of the Krebs cycle intermediate and anaplerotic substrate 2-oxoglutarate (2-OG, a-ketoglutarate). 17,18 Some types of human tumor cells exhibit an high requirement for Gln ("glutamine addiction") 15 and…”

Section: Introductionmentioning

confidence: 99%

Dependence on glutamine uptake and glutamine addiction characterize myeloma cells: a new attractive target

Bolzoni

Chiu

Accardi

et al. 2016

Blood

143

156

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Key Points• Myeloma cells produce ammonium in the presence of glutamine, showing high glutaminase and low glutamine synthetase expression.• Myeloma cells show high expression of glutamine transporters and inhibition of ASCT2 transporter hinders myeloma growth.The importance of glutamine (Gln) metabolism in multiple myeloma (MM) cells and its potential role as a therapeutic target are still unknown, although it has been reported that human myeloma cell lines (HMCLs) are highly sensitive to Gln depletion. In this study, we found that both HMCLs and primary bone marrow (BM) CD138 1 cells produced large amounts of ammonium in the presence of Gln. MM patients have lower BM plasma Gln with higher ammonium and glutamate than patients with indolent monoclonal gammopathies. Interestingly, HMCLs expressed glutaminase (GLS1) and were sensitive to its inhibition, whereas they exhibited negligible expression of glutamine synthetase (GS). High GLS1 and low GS expression were also observed in primary CD138 1 cells. Gln-free incubation or treatment with the glutaminolytic enzyme L-asparaginase depleted the cell contents of Gln, glutamate, and the anaplerotic substrate 2-oxoglutarate, inhibiting MM cell growth. Consistent with the dependence of MM cells on extracellular Gln, a gene expression profile analysis, on both proprietary and published datasets, showed an increased expression of the Gln transporters SNAT1, ASCT2, and LAT1 by CD138 1 cells across the progression of monoclonal gammopathies. Among these transporters, only ASCT2 inhibition in HMCLs caused a marked decrease in Gln uptake and a significant fall in cell growth. Consistently, stable ASCT2 downregulation by a lentiviral approach inhibited HMCL growth in vitro and in a murine model. In conclusion, MM cells strictly depend on extracellular Gln and show features of Gln addiction. Therefore, the inhibition of Gln uptake is a new attractive therapeutic strategy for MM. (Blood. 2016;128(5):667-679)

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“…The Myc family member, c-Myc, indirectly stimulates GLS1 expression in Burkitt's lymphoma and prostate cancer cells through suppression of microRNA-23a/b (15). In addition, the mammalian target of rapamycin pathway and the extracellular signal-regulated protein kinase pathway were also shown to be involved in tumor growth through the regulation of glutaminolysis (16,17). Due to the important role of GLS1 in cell survival, a number of small-molecule inhibitors targeting glutaminase have been developed, including bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) (18), compound 968 (19) and CB-839 (13).…”

Section: Introductionmentioning

confidence: 99%

Glutaminase sustains cell survival via the regulation of glycolysis and glutaminolysis in colorectal cancer

Zhang

Wei

et al. 2017

Oncology Letters

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Abstract. Cancer cells remodel their metabolic programs towards aerobic glycolysis and elevated glutaminolysis to meet the requirement s of rapid proliferation. Understanding how cells sense and adapt to these changes may provide new targets for therapeutic intervention. Deamination of glutamine to glutamate by glutaminase (GLS1) is an essential step in glutaminolysis. The present study revealed that the loss of GLS1 expression by RNA interference or inhibitor decreased the proliferation and viability of colorectal cancer (CRC) cells. The abrogation of GLS1 function notably inhibited glutaminolysis and aerobic glycolysis, which resulted in the decrease of internal ATP levels and an increase in cell death. In addition, GLS1 expression was significantly elevated in CRC tissues in comparison with adjacent normal tissues (P<0.001), which is associated with the cell differentiation status and tumor node metastasis stage. In conclusion, the present study defined a key role of GLS1 in coupling glutaminolysis with elevated glucose uptake and consequently the growth of colon cancer cells. Due to the functional importance of GLS1 in regulating cell metabolism, it was proposed that GLS1 may serve as a target for colorectal cancer therapy.

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Compensatory glutamine metabolism promotes glioblastoma resistance to mTOR inhibitor treatment

Cited by 202 publications

References 42 publications

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

Erratum: From Krebs to clinic: glutamine metabolism to cancer therapy

Dependence on glutamine uptake and glutamine addiction characterize myeloma cells: a new attractive target

Glutaminase sustains cell survival via the regulation of glycolysis and glutaminolysis in colorectal cancer

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