title: p53 regulates cell survival by inhibiting PIK3CA in squamous cell carcinomas.
abstract: Interactions between the p53 and PI3K/AKT pathways 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 p110alpha 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 of p53 are mutually exclusive events and either event is able to promote a malignant phenotype. Moreover, the negative effect of p53 induction on cell survival involves the transcriptional inhibition of PIK3CA that is independent of PTEN activity, 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 the PI3K/AKT prosurvival signal independent of PTEN in epithelial tumors. This inhibition is required for p53-mediated apoptosis in malignant cells.
authors.affiliation: Laboratory of Epithelial Cancer Biology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. singhb@mskcc.org
authors.forename: Bhuvanesh
authors.initials: B
authors.lastname: Singh
authors.forename: Pabbathi G
authors.initials: PG
authors.lastname: Reddy
authors.forename: Andy
authors.initials: A
authors.lastname: Goberdhan
authors.forename: Christine
authors.initials: C
authors.lastname: Walsh
authors.forename: Su
authors.initials: S
authors.lastname: Dao
authors.forename: Ivan
authors.initials: I
authors.lastname: Ngai
authors.forename: Ting Chao
authors.initials: TC
authors.lastname: Chou
authors.forename: Pornchai
authors.initials: P
authors.lastname: O-Charoenrat
authors.forename: Arnold J
authors.initials: AJ
authors.lastname: Levine
authors.forename: Pulivarthi H
authors.initials: PH
authors.lastname: Rao
authors.forename: Archontoula
authors.initials: A
authors.lastname: Stoffel
mesh_terms: D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D020134:Catalytic Domain / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004252:DNA Mutational Analysis; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism* / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C494918:AKT1 protein, human; C494929:PTEN protein, human