Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer
Menée sur des lignées cellulaires de cancer colorectal et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels un gène PI3KCA muté induit une dépendance à la glutamine des cellules cancéreuses
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.