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Mutant PIK3CA promotes cell growth and invasion of human cancer cells
Yardena Samuels1, Luis A Diaz, Oleg Schmidt-Kittler
1The Sidney Kimmel Comprehensive Cancer Center and The Howard Hughes Medical Institute, The Johns Hopkins University Medical Institutions, Baltimore, MD 21231, USA.
Abstract:
PIK3CA is mutated in diverse human cancers, but the functional effects of these mutations have not been defined. To evaluate the consequences of PIK3CA alterations, the two most common mutations were inactivated by gene targeting in colorectal cancer (CRC) cells. Biochemical analyses of these cells showed that mutant PIK3CA selectively regulated the phosphorylation of AKT and the forkhead transcription factors FKHR and FKHRL1. PIK3CA mutations had little effect on growth under standard conditions, but reduced cellular dependence on growth factors. PIK3CA mutations resulted in attenuation of apoptosis and facilitated tumor invasion. Treatment with the PI3K inhibitor LY294002 abrogated PIK3CA signaling and preferentially inhibited growth of PIK3CA mutant cells. These data have important implications for therapy of cancers harboring PIK3CA alterations.
Insights
Mutations in PIK3CA, common in cancers, reduce cell dependence on growth factors. This leads to less apoptosis and increased tumor invasion, offering therapeutic targets for PIK3CA-altered cancers.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- The gene PIK3CA is frequently altered in various human cancers.
- The functional consequences of PIK3CA mutations remain largely undefined.
Purpose of the Study:
- To investigate the functional impact of the two most common PIK3CA mutations in colorectal cancer (CRC).
Main Methods:
- Gene targeting was employed to inactivate common PIK3CA mutations in CRC cells.
- Biochemical analyses were performed to assess signaling pathway alterations.
Main Results:
- Mutant PIK3CA selectively regulated AKT and FKHR/FKHRL1 phosphorylation.
- PIK3CA mutations decreased growth factor dependence and attenuated apoptosis.
- Tumor invasion was facilitated by PIK3CA mutations.
- The PI3K inhibitor LY294002 abrogated PIK3CA signaling and inhibited growth of mutant cells.
Conclusions:
- PIK3CA mutations impact key cellular processes including apoptosis and invasion.
- Targeting PI3K signaling may be a viable therapeutic strategy for cancers with PIK3CA alterations.
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