Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer
Open accessAbstract
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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Cancer cells driven by oncogenic MYC, K-Ras, and PIK3CA require glutamine for survival and display extensive anabolic utilization of glutamine.
“Notably, cancer cells driven by oncogenic MYC, K-Ras, and PIK3CA require glutamine for their survival and display extensive anabolic utilization of glutamine29,174,175”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [175]
Oncogenic PIK3CA increases glutamine dependency by upregulating mitochondrial GPT2.
“Oncogenic PIK3CA increases the dependency of cancer cells on glutamine by upregulating the expression of mitochondrial GPT2, which catalyzes the transamination reaction that converts glutamate and pyruvate into α-KG and alanine175.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [175]
PIK3CA mutant colorectal cancer cells exhibit elevated anaplerotic α-KG production and ATP generation from glutamine compared with wild-type cells.
“Additionally, compared with wild-type cells, PIK3CA mutant colorectal cancer (CRC) cells exhibit elevated anaplerotic α-KG production and ATP generation from glutamine.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [175]
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“Oncogenic PIK3CA mutations were reported to reprogram glutamine metabolism in CRC [35].”
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- 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, N. J., Xu, Y., Conlon, R. A., Markowitz, S., Kinzler, K. W., Velculescu, V. E., Brunengraber, H., Willis, J. E., LaFramboise, T., Hatzoglou, M., Zhang, G.-F., Vogelstein, B., & Wang, Z.
- Affiliations
- Case Comprehensive Cancer Center (US)
- Howard Hughes Medical Institute (US)
- Case Western Reserve University (US)
- Wannan Medical College (CN)
- Army Medical University (CN)
- University Hospitals Cleveland Medical Center (US)
- Cleveland State University (US)
- Corresponding author
- Wang, Zhenghe
- ORCID
- Hao, Yujun
- Samuels, Yardena
- Li, Qingling
- Krokowski, Dawid
- Wang, Chao
- Jin, Zhicheng
- Feng, Xiujing
- Xiang, Min
- Xu, Claire
- Fink, Stephen
- Meropol, Neal J.
- Xu, Yan
- Conlon, Ronald A.
- Markowitz, Sanford
- Kinzler, Kenneth W.
- Velculescu, Victor E.
- Brunengraber, Henri
- Willis, Joseph E.
- LaFramboise, Thomas
- Hatzoglou, Maria
- Vogelstein, Bert
- Wang, Zhenghe
- Venue
- Nature Communications
- Published
- 2016-06-20
- Volume
- 7
- Issue
- 1
- Pages
- 11971-11971
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4915131
- OpenAlex
- W2464198273
- Cited by
- 290
- References
- 44
- Citations by year
- 2026: 16 · 2025: 30 · 2024: 34 · 2023: 44 · 2022: 45 · 2021: 28 · 2020: 22 · 2019: 28 · 2018: 22 · 2017: 16 · 2016: 5
- FWCI
- 9.99
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- EngagedScholarship @ Cleveland State University (Cleveland State University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (CA043703, R37‐DK060596, DK060596)
- National Cancer Institute (R01CA127590, R37CA043460, R21CA160060, R21CA181859, P50CA150964, P30CA043703, R01CA196643)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK053307, R37DK060596)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- PIK3CA mutation, colorectal cancer, glutamine metabolism, glutamine dependency, alpha-ketoglutarate, TCA cycle, p110α, aminooxyacetic acid, tumor growth
- MeSH terms
- Pyruvate Dehydrogenase Acetyl-Transferring Kinase, Adenocarcinoma, Adenosine Triphosphate, Aminooxyacetic Acid, Transaminases, Animals, Antineoplastic Agents, Citric Acid Cycle, Enzyme Inhibitors, Female, Glutamine, Humans, Ketoglutaric Acids, Mice, Nude, Mutation, Colorectal Neoplasms, Signal Transduction, Gene Expression Regulation, Neoplastic, Protein Serine-Threonine Kinases, HT29 Cells, Xenograft Model Antitumor Assays, HCT116 Cells, Cell Line, Tumor, Tumor Burden, Mice, Activating Transcription Factor 4, Class I Phosphatidylinositol 3-Kinases
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