Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer

被引：213

作者：

Hao, Yujun ^{[1
,2
]}

Samuels, Yardena ^{[3
,4
,5
]}

Li, Qingling ^{[6
]}

Krokowski, Dawid ^{[7
]}

Guan, Bo-Jhih ^{[7
]}

Wang, Chao ^{[1
,2
,15
]}

Jin, Zhicheng ^{[6
]}

Dong, Bohan ^{[1
,8
]}

Cao, Bo ^{[1
,9
]}

Feng, Xiujing ^{[1
,2
]}

Xiang, Min ^{[1
,10
]}

Xu, Claire ^{[11
]}

Fink, Stephen ^{[2
,12
]}

Meropol, Neal J. ^{[2
,12
]}

Xu, Yan ^{[13
]}

Conlon, Ronald A. ^{[1
,2
]}

Markowitz, Sanford ^{[2
,12
]}

Kinzler, Kenneth W. ^{[3
,4
]}

Velculescu, Victor E. ^{[3
,4
]}

Brunengraber, Henri ^{[6
]}

Willis, Joseph E. ^{[14
]}

LaFramboise, Thomas ^{[1
,2
]}

Hatzoglou, Maria ^{[7
]}

Zhang, Guo-Fang ^{[6
]}

Vogelstein, Bert ^{[3
,4
]}

Wang, Zhenghe ^{[1
,2
]}

机构：

[1] Case Western Reserve Univ, Dept Genet & Genome Sci, 10900 Euclid Ave, Cleveland, OH 44106 USA

[2] Case Western Reserve Univ, Case Comprehens Canc Ctr, 10900 Euclid Ave, Cleveland, OH 44106 USA

[3] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Ludwig Ctr, Baltimore, MD 21231 USA

[4] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Howard Hughes Med Inst, Baltimore, MD 21231 USA

[5] Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel

[6] Case Western Reserve Univ, Dept Nutr, 10900 Euclid Ave, Cleveland, OH 44106 USA

[7] Case Western Reserve Univ, Dept Pharmacol, Sch Med, 10900 Euclid Ave, Cleveland, OH 44106 USA

[8] Wannan Med Coll, Dept Biochem & Mol Biol, Wuhu 241000, Peoples R China

[9] Third Mil Med Univ, Dept Pharmacognosy, Sch Pharm, Chongqing 400038, Peoples R China

[10] Suzhou Hlth Coll, Dept Pharm, Suzhou 215009, Jiangsu, Peoples R China

[11] Hathaway Brown Sch, 19600 North Pk Blvd, Shaker Hts, OH 44122 USA

[12] Case Western Reserve Univ, Dept Med, Univ Hosp Case Med Ctr, 10900 Euclid Ave, Cleveland, OH 44106 USA

[13] Cleveland State Univ, Dept Chem, 2121 Euclid Ave, Cleveland, OH 44115 USA

[14] CaseWestern Reserve Univ, Dept Pathol, Univ Hosp Case Med Ctr, 10900 Euclid Ave, Cleveland, OH 44106 USA

[15] Natl Canc Ctr Singapore, Div Cellular & Mol Res, Singapore 169610, Singapore

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

关键词：

PHOSPHOINOSITIDE 3-KINASE PATHWAY; TUMOR-GROWTH; CELLS; KRAS; DEPRIVATION; EXPRESSION; GLUCOSE; PHOSPHORYLATION; PROLIFERATION; OPPORTUNITIES;

D O I：

10.1038/ncomms11971

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 alpha-ketoglutarate to replenish the tricarboxylic acid cycle and generate ATP. Mutant p110 alpha 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.

引用

页数：13

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