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; Zhenghe Wang

doi:10.1038/ncomms11971

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 BrunengraberJoseph E. Willis, Thomas Laframboise, Maria Hatzoglou, Guo Fang Zhang, Bert Vogelstein, Zhenghe Wang

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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.

Original language	English (US)
Article number	11971
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms11971
State	Published - Jun 20 2016

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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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, N. J., Xu, Y., Conlon, R. A., Markowitz, S., Kinzler, K. W., Velculescu, V. E., ... Wang, Z. (2016). Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer. Nature communications, 7, Article 11971. https://doi.org/10.1038/ncomms11971

Hao, Y, Samuels, Y, Li, Q, Krokowski, D, Guan, BJ, 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, GF, Vogelstein, B & Wang, Z 2016, 'Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer', Nature communications, vol. 7, 11971. https://doi.org/10.1038/ncomms11971

@article{78084a8350da481c964eb119d6afb077,

title = "Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer",

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.",

author = "Yujun Hao and Yardena Samuels and Qingling Li and Dawid Krokowski and Guan, {Bo Jhih} and Chao Wang and Zhicheng Jin and Bohan Dong and Bo Cao and Xiujing Feng and Min Xiang and Claire Xu and Stephen Fink and Meropol, {Neal J.} and Yan Xu and Conlon, {Ronald A.} and Sanford Markowitz and Kinzler, {Kenneth W.} and Velculescu, {Victor E.} and Henri Brunengraber and Willis, {Joseph E.} and Thomas Laframboise and Maria Hatzoglou and Zhang, {Guo Fang} and Bert Vogelstein and Zhenghe Wang",

note = "Funding Information: We thank Dr Anthony Wynshaw-Boris for critical reading of the manuscript. This work is supported by NIH grants R01CA196643, R21CA160060, R21CA181859, R01CA127590, P50CA150964 and P30 CA043703 (to Z.W.) and R37-DK060596 and R01-DK053307 (to M.H.).",

year = "2016",

month = jun,

day = "20",

doi = "10.1038/ncomms11971",

language = "English (US)",

volume = "7",

journal = "Nature communications",

issn = "2041-1723",

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T1 - Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer

AU - Hao, Yujun

AU - Samuels, Yardena

AU - Li, Qingling

AU - Krokowski, Dawid

AU - Guan, Bo Jhih

AU - Wang, Chao

AU - Jin, Zhicheng

AU - Dong, Bohan

AU - Cao, Bo

AU - Feng, Xiujing

AU - Xiang, Min

AU - Xu, Claire

AU - Fink, Stephen

AU - Meropol, Neal J.

AU - Xu, Yan

AU - Conlon, Ronald A.

AU - Markowitz, Sanford

AU - Kinzler, Kenneth W.

AU - Velculescu, Victor E.

AU - Brunengraber, Henri

AU - Willis, Joseph E.

AU - Laframboise, Thomas

AU - Hatzoglou, Maria

AU - Zhang, Guo Fang

AU - Vogelstein, Bert

AU - Wang, Zhenghe

N1 - Funding Information: We thank Dr Anthony Wynshaw-Boris for critical reading of the manuscript. This work is supported by NIH grants R01CA196643, R21CA160060, R21CA181859, R01CA127590, P50CA150964 and P30 CA043703 (to Z.W.) and R37-DK060596 and R01-DK053307 (to M.H.).

PY - 2016/6/20

Y1 - 2016/6/20

N2 - 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.

AB - 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.

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U2 - 10.1038/ncomms11971

DO - 10.1038/ncomms11971

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SN - 2041-1723

VL - 7

JO - Nature communications

JF - Nature communications

M1 - 11971

ER -

Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer

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