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

Oncogene volume 29, pages 3605–3618 (2010)Cite this article

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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.

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Abbreviations

PI3-kinase:

phosphoinositide 3-kinase

PKB/Akt:

protein kinase B/Akt

mTOR:

mammalian target of rapamycin

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Acknowledgements

KS is a Wellcome Trust International Senior Research Fellow. Infrastructural support by funding from ICMR, DBT, DST and UGC to MCB is acknowledged. RS gratefully acknowledges SRF from CSIR.

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  1. Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India

    R Suvasini & K Somasundaram

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  1. R Suvasini
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Correspondence to K Somasundaram.

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Suvasini, R., Somasundaram, K. Essential role of PI3-kinase pathway in p53-mediated transcription: Implications in cancer chemotherapy. Oncogene 29, 3605–3618 (2010). https://doi.org/10.1038/onc.2010.123

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