Metformin Decreases Glucose Oxidation and Increases the Dependency of Prostate Cancer Cells on Reductive Glutamine Metabolism

Fendt, Sarah-Maria; Bell, Eric L.; Keibler, Mark A.; Davidson, Shawn M.; Wirth, G.; Fiske, Brian P.; Mayers, Jared R.; Schwab, Matthias; Bellinger, Gary; Csibi, Alfredo; Patnaik, Akash; Blouin, Marie Jose; Cantley, Lewis C.; Guarente, Leonard; Blenis, John; Pollak, Michael; Olumi, Aria F.; Heiden, Matthew G. Vander; Stephanopoulos, Gregory

doi:10.1158/0008-5472.can-13-0080

Cited by 184 publications

(213 citation statements)

References 46 publications

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“…Consistently metformin, an inhibitor of mitochondrial complex I, provokes a decrease of proliferation with a subsequent activation of reductive glutamine metabolism in vitro and in a TRAMP mouse model [159,170]. Moreover, a combinatorial therapy of metformin and an inhibitor of glutamine metabolism might be promising for therapeutics, since PC-3 and DU-145 cell lines are reportedly glutamine addicted [171,172], and respiration and fatty acid biosynthesis could thus be inhibited simultaneously [170].…”

Section: Later Stage Prostate Cancer Metabolismmentioning

confidence: 97%

Organ-Specific Cancer Metabolism and Its Potential for Therapy

Elia

Schmieder

Christen

et al. 2015

Handbook of Experimental Pharmacology

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104

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KEYWORDS:Cancer metabolism, metabolic therapy, tissue specific metabolism, genetic drivers, epigenetic drivers, microenvironment, Warburg effect, reverse Warburg effect, mixed Warburg effect, triple-negative breast cancer, estrogen receptor positive breast cancer; prostate cancer, liver cancer, gluconeogenesis, fatty acid metabolism, glucose metabolism, glutamine metabolism, serine metabolism, metabolic normalization, metabolic depletion ABSTRACTTargeting the metabolism of cancer cells has the potential to lead to major advances in tumor therapy. Numerous promising metabolic drug targets have been identified. Yet, it has emerged that there is no singular metabolism that defines the oncogenic state of the cell. Rather, the metabolism of cancer cells is a function of the requirements of a tumor. Hence, the tissue of origin, the (epi)genetic drivers, aberrant signaling, and the microenvironment all together define these metabolic requirements. In this chapter we discuss in light of (epi)genetic, signaling, and environmental factors the diversity in cancer metabolism based on triple-negative and estrogen receptor positive breast cancer, early and late stage prostate cancer, and liver cancer. These types of cancer all display distinct and partially opposing metabolic behaviors (e.g. Warburg versus reverse Warburg metabolism). Yet, for each of the cancers their distinct metabolism supports the oncogenic phenotype. Finally, we will assess the therapeutic potential of metabolism based on the concepts of metabolic normalization and metabolic depletion.

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Section: Later Stage Prostate Cancer Metabolismmentioning

confidence: 97%

Organ-Specific Cancer Metabolism and Its Potential for Therapy

Elia

Schmieder

Christen

et al. 2015

Handbook of Experimental Pharmacology

Self Cite

104

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“…In addition, [1][2][3][4][5][6][7][8][9][10][11][12][13] C]glutamine labeling provides a more accurate measurement of reductive carboxylation of α-ketoglutarate to citrate, since this carbon is lost as carbon dioxide by α-ketodehydrogenase in the oxidative pathway but is retained if reductive carboxylation is active (27). By culturing stable C4-2 cells supplemented with [1][2][3][4][5][6][7][8][9][10][11][12][13] C]glutamine as tracers, we identified the enrichment of citrate m+1 in control cells expressing nontargeting shRNA (shNT), whereas ablation of SRC-2 showed a significant and robust decrease in the percentage of citrate m+1 ( Figure 2B). In addition, SRC-2 knockdown also decreased the levels of α-ketoglutarate m+1 ( Figure 2C), confirming that SRC-2 regulates the flow of carbon from glutamine to promote the reductive carboxylation of α-ketoglutarate in prostate cancer cells.…”

Section: Src-2 Regulates Lipogenesis By Reductive Glutamine Metabolismentioning

confidence: 99%

Coactivator SRC-2–dependent metabolic reprogramming mediates prostate cancer survival and metastasis

Dasgupta¹,

Putluri²,

Long³

et al. 2015

J. Clin. Invest.

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“…As AMPK negatively regulates glucose consumption in cancer cells (Faubert et al 2013), the effect of metformin on AMPK phosphorylation was associated with a significant doseand time-dependent reduction in FDG uptake. In a mouse model of prostate cancer, it has been shown that the decreased glucose oxidation exerted by metformin induces the dependency on reductive glutamine metabolism, which is an important source of cellular energy (Fendt et al 2013). Glutamine is a substrate in the production of biochemical intermediates for the tricarboxylic acid (TCA) cycle.…”

Section: Metformin's Effect On Glucose Uptake: Fluoro-deoxy-glucose Imentioning

confidence: 99%

Metformin, cancer and glucose metabolism

Salani¹,

Río²,

Marini³

et al. 2014

Endocrine-Related Cancer

104

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Metformin is the first-line treatment for type 2 diabetes. Results from several clinical studies have indicated that type 2 diabetic patients treated with metformin might have a lower cancer risk. One of the primary metabolic changes observed in malignant cell transformation is an increased catabolic glucose metabolism. In this context, once it has entered the cell through organic cation transporters, metformin decreases mitochondrial respiration chain activity and ATP production that, in turn, activates AMP-activated protein kinase, which regulates energy homeostasis. In addition, metformin reduces cellular energy availability and glucose entrapment by inhibiting hexokinase-II, which catalyses the glucose phosphorylation reaction. In this review, we discuss recent findings on molecular mechanisms that sustain the anticancer effect of metformin through regulation of glucose metabolism. In particular, we have focused on the emerging action of metformin on glycolysis in normal and cancer cells, with a drug discovery perspective.

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Metformin Decreases Glucose Oxidation and Increases the Dependency of Prostate Cancer Cells on Reductive Glutamine Metabolism

Cited by 184 publications

References 46 publications

Organ-Specific Cancer Metabolism and Its Potential for Therapy

Organ-Specific Cancer Metabolism and Its Potential for Therapy

Coactivator SRC-2–dependent metabolic reprogramming mediates prostate cancer survival and metastasis

Metformin, cancer and glucose metabolism

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