p53 regulates cell survival by inhibiting PIK3CA in squamous cell carcinomas
- Bhuvanesh Singh1,5,
- Pabbathi G. Reddy1,
- Andy Goberdhan1,
- Christine Walsh3,
- Su Dao1,
- Ivan Ngai1,
- Ting Chao Chou2,
- Pornchai O-charoenrat1,
- Arnold J. Levine3,
- Pulivarthi H. Rao4, and
- Archontoula Stoffel3,5
- 1Laboratory of Epithelial Cancer Biology and 2Preclinical Pharmacology Core Facility, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA; 3Laboratory of Cancer Biology, Rockefeller University, New York, New York 10021, USA; 4Children's Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.
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.
Keywords
Footnotes
-
↵5 Corresponding authors.
-
E-MAIL singhb{at}mskcc.org; FAX (212) 717-3302.
-
E-MAIL stoffea{at}rockvax.rockefeller.edu; FAX (212) 327-7058.
-
Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.973602.
-
- Received December 31, 2001.
- Accepted February 22, 2002.
- Cold Spring Harbor Laboratory Press
