p53 regulates cell survival by inhibiting PIK3CA in squamous cell carcinomas

Abstract

Interactions between the p53 and PI3K/AKTpathways play a significant role in the determination of cell death/survival. In benign cells these pathways are interrelated through the transcriptional regulation of PTEN by p53, which is required for p53-mediated apoptosis. PTEN exerts its effects by decreasing the phosphorylated AKT fraction, thereby diminishing prosurvival activities. However, the link between these pathways in cancer is not known. In this study, PIK3CA, encoding the p110α catalytic subunit of PI3K, is identified as an oncogene involved in upper aerodigestive tract (UADT) carcinomas. Simultaneous abnormalities in both pathways are rare in primary tumors, suggesting that amplification of PIK3CA and mutation ofp53 are mutually exclusive events and either event is able to promote a malignant phenotype. Moreover, the negative effect ofp53 induction on cell survival involves the transcriptional inhibition of PIK3CA that is independent of PTENactivity, as PTEN is not expressed in the primary tumors. Conversely, constitutive activation of PIK3CA results in resistance to p53-related apoptosis in PTEN deficient cells. Thus, p53 regulates cell survival by inhibiting thePI3K/AKT prosurvival signal independent of PTENin epithelial tumors. This inhibition is required for p53-mediated apoptosis in malignant cells.