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Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer.
- Source :
-
Nature communications [Nat Commun] 2016 Jun 20; Vol. 7, pp. 11971. Date of Electronic Publication: 2016 Jun 20. - Publication Year :
- 2016
-
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.
- Subjects :
- Activating Transcription Factor 4 genetics
Activating Transcription Factor 4 metabolism
Adenocarcinoma drug therapy
Adenocarcinoma enzymology
Adenocarcinoma pathology
Adenosine Triphosphate antagonists & inhibitors
Adenosine Triphosphate biosynthesis
Aminooxyacetic Acid pharmacology
Animals
Antineoplastic Agents pharmacology
Cell Line, Tumor
Citric Acid Cycle drug effects
Class I Phosphatidylinositol 3-Kinases antagonists & inhibitors
Class I Phosphatidylinositol 3-Kinases metabolism
Colorectal Neoplasms drug therapy
Colorectal Neoplasms enzymology
Colorectal Neoplasms pathology
Enzyme Inhibitors pharmacology
Female
Glutamine antagonists & inhibitors
HCT116 Cells
HT29 Cells
Humans
Ketoglutaric Acids antagonists & inhibitors
Ketoglutaric Acids metabolism
Mice
Mice, Nude
Protein Serine-Threonine Kinases genetics
Protein Serine-Threonine Kinases metabolism
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
Signal Transduction
Transaminases genetics
Transaminases metabolism
Tumor Burden drug effects
Xenograft Model Antitumor Assays
Adenocarcinoma genetics
Class I Phosphatidylinositol 3-Kinases genetics
Colorectal Neoplasms genetics
Gene Expression Regulation, Neoplastic
Glutamine metabolism
Mutation
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 7
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 27321283
- Full Text :
- https://doi.org/10.1038/ncomms11971