Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer

Yujun Hao, Yardena Samuels, Qingling Li, Dawid Krokowski, Bo-Jhih Guan, Chao Wang, Zhicheng Jin, Bohan Dong, Bo Cao, Xiujing Feng, Min Xiang, Claire Xu, Stephen Fink, Neal J. Meropol, Yan Xu, Ronald A. Conlon, Sanford Markowitz, Kenneth W. Kinzler, Victor E. Velculescu, Henri Brunengraber, Joseph E. Willis, Thomas LaFramboise, Maria Hatzoglou, Guo-Fang Zhang, Bert Vogelstein and Zhenghe Wang ()
Additional contact information
Yujun Hao: Case Western Reserve University
Yardena Samuels: Ludwig Center and Howard Hughes Medical Institute, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Qingling Li: Case Western Reserve University
Dawid Krokowski: School of Medicine, Case Western Reserve University
Bo-Jhih Guan: School of Medicine, Case Western Reserve University
Chao Wang: Case Western Reserve University
Zhicheng Jin: Case Western Reserve University
Bohan Dong: Case Western Reserve University
Bo Cao: Case Western Reserve University
Xiujing Feng: Case Western Reserve University
Min Xiang: Case Western Reserve University
Claire Xu: Hathaway Brown School
Stephen Fink: Case Comprehensive Cancer Center, Case Western Reserve University
Neal J. Meropol: Case Comprehensive Cancer Center, Case Western Reserve University
Yan Xu: Cleveland State University
Ronald A. Conlon: Case Western Reserve University
Sanford Markowitz: Case Comprehensive Cancer Center, Case Western Reserve University
Kenneth W. Kinzler: Ludwig Center and Howard Hughes Medical Institute, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Victor E. Velculescu: Ludwig Center and Howard Hughes Medical Institute, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Henri Brunengraber: Case Western Reserve University
Joseph E. Willis: University Hospitals Case Medical Center, Case Western Reserve University
Thomas LaFramboise: Case Western Reserve University
Maria Hatzoglou: School of Medicine, Case Western Reserve University
Guo-Fang Zhang: Case Western Reserve University
Bert Vogelstein: Ludwig Center and Howard Hughes Medical Institute, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Zhenghe Wang: Case Western Reserve University

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11971

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