Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer

Hao, Yujun; Samuels, Yardena; Li, Qingling; Krokowski, Dawid; Guan, Bo; Wang, Chao; Jin, Zhicheng; Dong, Bohan; Cao, Bo; Feng, Xiujing; Xiang, Min; Xu, Claire; Fink, Stephen P.; Meropol, Neal J.; Xu, Yan; Conlon, Ron A; Markowitz, Sanford D.; Kinzler, Kenneth W.; Velculescu, Victor E.; Brunengraber, Henri; Willis, Joseph E.; LaFramboise, Thomas; Hatzoglou, Maria; Zhang, Guofang; Vogelstein, Bert; Wang, Benlian

doi:10.1038/ncomms11971

Cited by 224 publications

(232 citation statements)

References 44 publications

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“…The oncogenic protein MYC directly stimulates catabolic metabolism of glutamine by inducing expression of both glutamine transporter SLC1A5 and GLS genes (31); of note, GLS inhibition and glutamine deprivation halt proliferation of MYC-overexpressing tumor cells (30, 31). A recent paper has also shown increased oxidative metabolism of glutamine in PI3K -mutated, but not PI3K -WT, colorectal cancers (32). On the other hand, different studies suggest that glutamine uptake may be nonessential for in vivo GBM and lung tumors, in which glucose utilization is likely sufficient to satisfy both energetic and anaplerotic needs (11, 12, 33).…”

Section: Metabolic Pathways That Sustain Cancer Cell Survival and Promentioning

confidence: 99%

“…Inhibitors of GLS, including BPTES and CB-839, GDH, such as GPNA or EGCG, or transaminases (TAs), such as aminooxyacetate (AOA), could all target the first steps of intracellular glutamine metabolism (32, 158). In a recent study, CB-839 reduced production of glutamine-derived glutamate, glutathione and TCA intermediates, and displayed significant antitumor activity against TNBC cell lines (159).…”

Section: Pharmacological Interventionsmentioning

confidence: 99%

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Targeting Cancer Metabolism: Dietary and Pharmacologic Interventions

et al. 2016

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Most tumors display oncogene-driven reprogramming of several metabolic pathways, which are crucial to sustain their growth and proliferation. In recent years, both dietary and pharmacological approaches that target deregulated tumor metabolism are beginning to be considered for clinical applications. Dietary interventions exploit the ability of nutrient-restricted conditions to exert broad biological effects, protecting normal cells, organs and systems, while sensitizing a wide variety of cancer cells to cytotoxic therapies. On the other hand, drugs targeting enzymes or metabolites of crucial metabolic pathways can be highly specific and effective, but must be matched with a responsive tumor, which might rapidly adapt. In this Review, we illustrate how dietary and pharmacological therapies differ in their effect on tumor growth, proliferation and metabolism, and discuss the available preclinical and clinical evidence in favor or against each of them. We also indicate, when appropriate, how to optimize future investigations on metabolic therapies on the basis of tumor- and patient-related characteristics.

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Section: Metabolic Pathways That Sustain Cancer Cell Survival and Promentioning

confidence: 99%

Section: Pharmacological Interventionsmentioning

confidence: 99%

Targeting Cancer Metabolism: Dietary and Pharmacologic Interventions

et al. 2016

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“…To this end, PIK3CA mutant colorectal cancer cell lines were recently shown to up-regulate the glutamate pyruvate transaminase 2 (GPT2) to fuel the TCA cycle with 2OG generated from pyruvate and glutamate (46). Notably, this role for GPT2 within PIK3CA mutant colon cancer cells was determined under glutamine depletion; this represents an alternative pathway for pyruvate and glutamate to sustain the TCA cycle that would parallel the widely appreciated anaplerotic roles of pyruvate to generate oxaloacetate through pyruvate carboxylase and glutamate dehydrogenase to generate 2OG.…”

Section: Discussionmentioning

confidence: 99%

PIK3CA mutant tumors depend on oxoglutarate dehydrogenase

Ilić

Birsoy

Aguirre

et al. 2017

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

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Oncogenic PIK3CA mutations are found in a significant fraction of human cancers, but therapeutic inhibition of PI3K has only shown limited success in clinical trials. To understand how mutant PIK3CA contributes to cancer cell proliferation, we used genome scale lossof-function screening in a large number of genomically annotated cancer cell lines. As expected, we found that PIK3CA mutant cancer cells require PIK3CA but also require the expression of the TCA cycle enzyme 2-oxoglutarate dehydrogenase (OGDH). To understand the relationship between oncogenic PIK3CA and OGDH function, we interrogated metabolic requirements and found an increased reliance on glucose metabolism to sustain PIK3CA mutant cell proliferation. Functional metabolic studies revealed that OGDH suppression increased levels of the metabolite 2-oxoglutarate (2OG). We found that this increase in 2OG levels, either by OGDH suppression or exogenous 2OG treatment, resulted in aspartate depletion that was specifically manifested as auxotrophy within PIK3CA mutant cells. Reduced levels of aspartate deregulated the malate-aspartate shuttle, which is important for cytoplasmic NAD + regeneration that sustains rapid glucose breakdown through glycolysis. Consequently, because PIK3CA mutant cells exhibit a profound reliance on glucose metabolism, malate-aspartate shuttle deregulation leads to a specific proliferative block due to the inability to maintain NAD + /NADH homeostasis. Together these observations define a precise metabolic vulnerability imposed by a recurrently mutated oncogene.

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“…Some breast cancer cells are known to catabolize glutamate primarily via transaminases, thus conserving the amine nitrogen [59]. Alanine transaminase 2 (GPT2), in particular, is critical for α-KG generation and therefore for glutamine/glutamate-mediated TCA cycle anaplerosis in colon cancer cells [60, 61]. In contrast to proliferative cells, transaminase expression is low in quiescent cells, and instead GLUD expression is induced [62].…”

Section: The Metabolic Fate Of Glutamate In Cancermentioning

confidence: 99%

Glutamine Metabolism in Cancer: Understanding the Heterogeneity

et al. 2017

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Reliance on glutamine has long been considered a hallmark of cancer cell metabolism. However, some recent studies have challenged this notion in vivo, prompting a need for further clarifications on the role of glutamine metabolism in cancer. We find that there is ample evidence of an essential role for glutamine in tumors and that a variety of factors, including tissue type, the underlying cancer genetics, the tumor microenvironment and other variables such as diet and host physiology collectively influence the role of glutamine in cancer. Thus the requirements for glutamine in cancer are overall highly heterogeneous. In this review, we discuss the implications both for basic science and for targeting glutamine metabolism in cancer therapy.

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Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer

Cited by 224 publications

References 44 publications

Targeting Cancer Metabolism: Dietary and Pharmacologic Interventions

Targeting Cancer Metabolism: Dietary and Pharmacologic Interventions

PIK3CA mutant tumors depend on oxoglutarate dehydrogenase

Glutamine Metabolism in Cancer: Understanding the Heterogeneity

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