Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Hao, Y; Samuels, Y; Li, Q; Krokowski, D; Guan, B-J; Wang, C; Jin, Z; Dong, B; Cao, B; Feng, X; Xiang, M; Xu, C; Fink, S; Meropol, NJ; Xu, Y; Conlon, RA; Markowitz, S; Kinzler, KW; Velculescu, VE; Brunengraber, H; Willis, JE; LaFramboise, T; Hatzoglou, M; Zhang, G-F; Vogelstein, B; Wang, Z

Published Date

  • June 20, 2016

Published In

Volume / Issue

  • 7 /

Start / End Page

  • 11971 -

PubMed ID

  • 27321283

Pubmed Central ID

  • PMC4915131

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/ncomms11971


  • eng

Conference Location

  • England