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Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer.

ABSTRACT: Cancer cells often require glutamine for growth, thereby distinguishing them from most normal cells. Here we show that PIK3CA mutations reprogram glutamine metabolism by upregulating glutamate pyruvate transaminase 2 (GPT2) in colorectal cancer (CRC) cells, making them more dependent on glutamine. Compared with isogenic wild-type (WT) cells, PIK3CA mutant CRCs convert substantially more glutamine to ?-ketoglutarate to replenish the tricarboxylic acid cycle and generate ATP. Mutant p110? upregulates GPT2 gene expression through an AKT-independent, PDK1-RSK2-ATF4 signalling axis. Moreover, aminooxyacetate, which inhibits the enzymatic activity of aminotransferases including GPT2, suppresses xenograft tumour growth of CRCs with PIK3CA mutations, but not with WT PIK3CA. Together, these data establish oncogenic PIK3CA mutations as a cause of glutamine dependency in CRCs and suggest that targeting glutamine metabolism may be an effective approach to treat CRC patients harbouring PIK3CA mutations.

SUBMITTER: Hao Y

PROVIDER: S-EPMC4915131 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer.

Hao Yujun Y Samuels Yardena Y Li Qingling Q Krokowski Dawid D Guan Bo-Jhih BJ Wang Chao C Jin Zhicheng Z Dong Bohan B Cao Bo B Feng Xiujing X Xiang Min M Xu Claire C Fink Stephen S Meropol Neal J NJ Xu Yan Y Conlon Ronald A RA Markowitz Sanford S Kinzler Kenneth W KW Velculescu Victor E VE Brunengraber Henri H Willis Joseph E JE LaFramboise Thomas T Hatzoglou Maria M Zhang Guo-Fang GF Vogelstein Bert B Wang Zhenghe Z

Nature communications 20160620

Cancer cells often require glutamine for growth, thereby distinguishing them from most normal cells. Here we show that PIK3CA mutations reprogram glutamine metabolism by upregulating glutamate pyruvate transaminase 2 (GPT2) in colorectal cancer (CRC) cells, making them more dependent on glutamine. Compared with isogenic wild-type (WT) cells, PIK3CA mutant CRCs convert substantially more glutamine to α-ketoglutarate to replenish the tricarboxylic acid cycle and generate ATP. Mutant p110α upregula ...[more]

PMID: 27321283

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Project description:Energy metabolism reprogramming is becoming an increasingly important hallmark of cancer. Specifically, cancers tend to undergo metabolic reprogramming to upregulate a cell‑dependent glutamine (Gln) metabolism. Notably, hepatocellular cell adhesion molecule (HepaCAM) has been previously reported to serve a key role as a tumour suppressor. However, the possible regulatory role of HepaCAM in Gln metabolism in prostate cancer (PCa) remains poorly understood. In the present study, bioinformatics analysis predicted a significant negative correlation among the expression of HepaCAM, phosphatidylinositol‑4,5‑bisphosphate 3‑kinase catalytic subunit α (PIK3CA), glutaminase (GLS) and solute carrier family 1 member 5 (SLC1A5), components of Gln metabolism, in clinical and genomic datasets. Immunohistochemistry results verified a negative correlation between HepaCAM and PIK3CA expression in PCa tissues. Subsequently, liquid chromatography‑tandem mass spectrometry (LC‑MS/MS) and gas chromatography‑mass spectrometry (GC‑MS) assays were performed, and the results revealed markedly reduced levels of Gln and metabolic flux in the blood samples of patients with PCa and in PCa cells. Mechanistically, overexpression of HepaCAM inhibited Gln metabolism and proliferation by regulating PIK3CA in PCa cells. In addition, Gln metabolism was discovered to be stress‑resistant in PCa cells, since the expression levels of GLS and SLC1A5 remained high for a period of time after Gln starvation. However, overexpression of HepaCAM reversed this resistance to some extent. Additionally, alpelisib, a specific inhibitor of PIK3CA, effectively potentiated the inhibitory effects of HepaCAM overexpression on Gln metabolism and cell proliferation through mass spectrometry and CCK‑8 experiments. In addition, the inhibitory effect of PIK3CA on the growth of tumor tissue in nude mice was also confirmed by immunohistochemistry in vivo. To conclude, the results from the present study revealed an abnormal Gln metabolic profile in the blood samples of patients with PCa, suggesting that it can be applied as a clinical diagnostic tool for PCa. Additionally, a key role of the HepaCAM/PIK3CA axis in regulating Gln metabolism, cell proliferation and tumour growth was identified. The combination of alpelisib treatment with the upregulation of HepaCAM expression may serve as a novel method for treating patients with PCa.

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Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer.

Publications

Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer.

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