Essential role of PI3-kinase pathway in p53-mediated transcription: Implications in cancer chemotherapy

Suvasini, R and Somasundaram, K (2010) Essential role of PI3-kinase pathway in p53-mediated transcription: Implications in cancer chemotherapy. In: Oncogene, 29 (25). pp. 3605-3618.

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Abstract

The PI3-kinase pathway is the target of inactivation in achieving better cancer chemotherapy. Here, we report that p53-mediated transcription is inhibited by pharmacological inhibitors and a dominant-negative mutant of PI3-kinase, and this inhibition was relieved by a constitutively active mutant of PI3-kinase. Akt/PKB and mTOR, the downstream effectors of PI3-kinase, were also found to be essential. LY294002 (PI3-kinase inhibitor) pre-treatment altered the post-translational modifications and the sub-cellular localization of p53. Although LY294002 increased the chemosensitivity of cells to low concentrations of adriamycin (adriamycin-low), it protected the cells from cytotoxicity induced by high concentrations of adriamycin (adriamycin-high) in a p53-dependent manner. Further, we found that LY294002 completely abolished the activation of p53 target genes (particularly pro-apoptotic) under adriamycin-high conditions, whereas it only marginally repressed the p53 target genes under adriamycin-low conditions; in fact, it further activated the transcription of NOXA, HRK, APAF1 and CASP5 genes. Thus, the differential effect of PI3-kinase on p53 functions seems to be responsible for the differential regulation of DNA damage-induced cytotoxicity and cell death by PI3-kinase. Our finding becomes relevant in the light of ongoing combination chemotherapy trials with the PI3-kinase pathway inhibitors and underscores the importance of p53 status in the careful formulation of combination chemotherapies. Oncogene (2010) 29, 3605-3618; doi: 10.1038/onc.2010.123; published online 26 April 2010

Item Type:	Journal Article
Publication:	Oncogene
Publisher:	Nature Publishing Group
Additional Information:	Copyright of this article belongs to Nature Publishing Group.
Keywords:	p53;PI3-kinase;chemosensitivity;chemotherapy
Department/Centre:	Division of Biological Sciences > Microbiology & Cell Biology
Date Deposited:	13 Jul 2010 06:15
Last Modified:	19 Sep 2010 06:11
URI:	http://eprints.iisc.ac.in/id/eprint/29190

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