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Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer

Author

Listed:
  • Yujun Hao

    (Case Western Reserve University
    Case Comprehensive Cancer Center, Case Western Reserve University)

  • Yardena Samuels

    (Ludwig Center and Howard Hughes Medical Institute, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
    The Weizmann Institute of Science)

  • 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
    Case Comprehensive Cancer Center, Case Western Reserve University
    Present address: Division of Cellular & Molecular Research, National Cancer Center Singapore, Singapore 169610, Singapore.)

  • Zhicheng Jin

    (Case Western Reserve University)

  • Bohan Dong

    (Case Western Reserve University
    Wannan Medical College)

  • Bo Cao

    (Case Western Reserve University
    School of Pharmacy, Third Military Medical University)

  • Xiujing Feng

    (Case Western Reserve University
    Case Comprehensive Cancer Center, Case Western Reserve University)

  • Min Xiang

    (Case Western Reserve University
    Suzhou Health College)

  • Claire Xu

    (Hathaway Brown School)

  • Stephen Fink

    (Case Comprehensive Cancer Center, Case Western Reserve University
    University Hospitals Case Medical Center, Case Western Reserve University)

  • Neal J. Meropol

    (Case Comprehensive Cancer Center, Case Western Reserve University
    University Hospitals Case Medical Center, Case Western Reserve University)

  • Yan Xu

    (Cleveland State University)

  • Ronald A. Conlon

    (Case Western Reserve University
    Case Comprehensive Cancer Center, Case Western Reserve University)

  • Sanford Markowitz

    (Case Comprehensive Cancer Center, Case Western Reserve University
    University Hospitals Case Medical 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
    Case Comprehensive Cancer Center, 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
    Case Comprehensive Cancer Center, Case Western Reserve University)

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.

Suggested Citation

  • 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 & Ya, 2016. "Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer," Nature Communications, Nature, vol. 7(1), pages 1-13, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11971
    DOI: 10.1038/ncomms11971
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    Cited by:

    1. Yujun Hao & Baoyu He & Liping Wu & Yamu Li & Chao Wang & Ting Wang & Longci Sun & Yanhua Zhang & Yangyang Zhan & Yiqing Zhao & Sanford Markowitz & Martina Veigl & Ronald A. Conlon & Zhenghe Wang, 2022. "Nuclear translocation of p85β promotes tumorigenesis of PIK3CA helical domain mutant cancer," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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