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Nat Commun. 2016 Jun 20;7:11971. doi: 10.1038/ncomms11971.

Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer.

Author information

1
Department of Genetics and Genome Sciences, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
2
Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
3
Ludwig Center and Howard Hughes Medical Institute, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USA.
4
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
5
Department of Nutrition, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
6
Department of Pharmacology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
7
Department of Biochemistry and Molecular Biology, Wannan Medical College, Wuhu 241000, China.
8
Department of Pharmacognosy, School of Pharmacy, Third Military Medical University, Chongqing 400038, China.
9
Department of Pharmacy, Suzhou Health College, Suzhou, Jiangsu 215009, China.
10
Hathaway Brown School, 19600 North Park Boulevard, Shaker Heights, Ohio 44122, USA.
11
Department of Medicine, University Hospitals Case Medical Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
12
Department of Chemistry, Cleveland State University, 2121 Euclid Avenue, Cleveland, Ohio 44115, USA.
13
Department of Pathology, University Hospitals Case Medical Center, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.

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 α-ketoglutarate to replenish the tricarboxylic acid cycle and generate ATP. Mutant p110α 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.

PMID:
27321283
PMCID:
PMC4915131
DOI:
10.1038/ncomms11971
[Indexed for MEDLINE]
Free PMC Article

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