Metabolic reprogramming in cancer: Unraveling the role of glutamine in tumorigenesis

Daye, Dania; Wellen, Kathryn E.

doi:10.1016/j.semcdb.2012.02.002

Cited by 331 publications

(265 citation statements)

References 89 publications

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“…Our data strongly argue that FLT3 is a major driver of anabolic metabolism, consistent with the normal role of FLT3 in promoting the robust proliferation of early hematopoietic progenitor cells (45). Many tumor cells are highly dependent on glutamine for glutaminolysis, a mitochondrial pathway producing glutamate, which can then be converted into α-ketoglutarate to fuel the TCA cycle or used as a precursor for glutathione synthesis (46,47). Deficient glutamine uptake could account for the decline in glutamine/glutamate levels we observed in AML cells on FLT3 inhibition and the impaired glutathione production that makes them hypersensitive to oxidative stress.…”

Section: Discussionsupporting

confidence: 78%

ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

Gregory

D’Alessandro

Alvarez-Calderon

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are common in acute myeloid leukemia (AML) and drive leukemic cell growth and survival. Although FLT3 inhibitors have shown considerable promise for the treatment of AML, they ultimately fail to achieve long-term remissions as monotherapy. To identify genetic targets that can sensitize AML cells to killing by FLT3 inhibitors, we performed a genome-wide RNA interference (RNAi)-based screen that identified ATM (ataxia telangiectasia mutated) as being synthetic lethal with FLT3 inhibitor therapy. We found that inactivating ATM or its downstream effector glucose 6-phosphate dehydrogenase (G6PD) sensitizes AML cells to FLT3 inhibitor induced apoptosis. Examination of the cellular metabolome showed that FLT3 inhibition by itself causes profound alterations in central carbon metabolism, resulting in impaired production of the antioxidant factor glutathione, which was further impaired by ATM or G6PD inactivation. Moreover, FLT3 inhibition elicited severe mitochondrial oxidative stress that is causative in apoptosis and is exacerbated by ATM/G6PD inhibition. The use of an agent that intensifies mitochondrial oxidative stress in combination with a FLT3 inhibitor augmented elimination of AML cells in vitro and in vivo, revealing a therapeutic strategy for the improved treatment of FLT3 mutated AML.A cute myeloid leukemia (AML) is a hematological cancer that is characterized by the aberrant growth of myeloid progenitor cells with a block in cellular differentiation. AML is the most common adult acute leukemia and accounts for ∼20% of childhood leukemias. Although frontline treatment of AML with cytotoxic chemotherapy achieves high remission rates, 75-80% of patients will either not respond to or will relapse after initial therapy, and most patients will die of their disease (1, 2). Thus, more effective and less toxic therapies for AML are required. The promise of molecularly targeted cancer therapies has generated much excitement with the remarkable clinical success of the small molecule tyrosine kinase inhibitors (TKIs) targeting the oncogenic kinase BCR-ABL for the treatment of chronic myeloid leukemia (3). However, targeted approaches for the treatment of AML have not yet yielded major successes.In AML, aberrant signal transduction drives the proliferation and survival of leukemic cells. Activated signal transduction occurs through genetic alterations of signaling molecules such as FLT3, KIT, PTPN11, and members of the RAS family (4, 5). Given the successful development and utilization of numerous TKIs, the FLT3 receptor tyrosine kinase has emerged as a promising target for the treatment of AML. Indeed, activating mutations in FLT3 are one of the most frequently observed genetic defects in AML and are comprised predominantly of internal tandem duplication (ITD) mutations in the juxtamembrane domain (6). FLT3-ITD mutations are associated with poor prognosis, including increased relapse rate, decreased disease-free survival, and poor overall survival (5,7,8). The cl...

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Section: Discussionsupporting

confidence: 78%

ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

Gregory

D’Alessandro

Alvarez-Calderon

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Finally, GLUL transcripts were only detected in CEM cells. Increased glutaminolysis relative to normal proliferating cells is a key characteristic of proliferating cancer cells (14,42). However, although CEM/R2 cells lack GLUL transcripts and exhibit reduced levels of transcripts for the glutamine metabolism genes ASNS, ASS1, and the glutamine transporter gene SLC1A5, it appears that they are less dependent on glutamine metabolism than non-resistant CEM cells (Fig.…”

Section: Discussionmentioning

confidence: 98%

Rewired Metabolism in Drug-resistant Leukemia Cells

Stäubert

Bhuiyan

Lindahl

et al. 2015

Journal of Biological Chemistry

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Background: Drug resistance is a common problem in cancer chemotherapy. Results: Transcriptomic and metabolomic data show that resistant leukemia cells exhibit reduced glutamine dependence, enhanced glucose dependence, and altered fatty acid metabolism. Conclusion:The metabolism of resistant leukemia cells is fundamentally rewired. Significance: Understanding the metabolic cost of resistance can lead to novel therapeutic strategies.

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“…In addition to glucose, increased glutamine uptake is another tumor-specific metabolic alteration [8,9]. Glutamine is first converted to glutamate by glutaminase and then deaminated to produce -ketoglutarate (α-KG) to enter the TCA cycle by either a transaminase or glutamate dehydrogenase.…”

Section: Cancer Cells Reprogram Metabolism For Proliferationmentioning

confidence: 99%

Metabolic alteration in tumorigenesis

Yang

Guan

2013

Sci. China Life Sci.

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Altered metabolism in cancer was first discovered by Otto Warburg early last century. Although the Warburg Effect has been widely used in tumor detection, relatively little progress had been made in mechanistic understanding of cancer metabolism in the subsequent eight decades. Genetic studies have recently identified mutations in human cancer targeting multiple enzymes involved in intermediate metabolism. One emerging mechanism common to these mutant enzymes is the accumulation of a metabolite that alters the epigenetic control. Otto Warburg [1,2] first discovered that cancer cells displayed enhanced glucose uptake and aerobic glycolysis, a phenomenon often referred as the Warburg Effect nowadays. Although the mechanism underlying the Warburg Effect is still not fully understood, increased uptake of glucose provides the basis to exploit its clinical application by 18 F-deoxyglucose positron emission tomography (PET) for tumor detection [3,4]. Decades after the Warburg Effect was discovered, the mechanistic insights of how metabolic alterations contribute to tumorigenesis are just emerging. Recent studies have revealed that eight metabolic genes, FH, SDHA, SDHB, SDHC, SDHD, SDHAF2, IDH1 and IDH2, encoding for subunits of four different metabolic enzymes, fumarate hydratase (FH), succinate dehydrogenase (SDH), and isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), were mutated in a number of human cancers [5]. These findings provide compelling genetic evidence supporting the notion that altered metabolism contributes to, as opposed to the consequence of, tumorigenesis. Here, we first briefly discuss how metabolism is reprogrammed to support cancer cell proliferation. We then focus on one emerging mechanism that is common to the mutations targeting all four metabolic enzymes in accumulating a metabolite to alter the epigenetic modifications in human cancer.

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Metabolic reprogramming in cancer: Unraveling the role of glutamine in tumorigenesis

Cited by 331 publications

References 89 publications

ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

Rewired Metabolism in Drug-resistant Leukemia Cells

Metabolic alteration in tumorigenesis

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