Repression of cancer cell senescence by PKCι

Senescence is an irreversible growth arrest phenotype adopted by cells that has a key role in protecting organisms from cancer. There is now considerable interest in therapeutic strategies that reactivate this process to control the growth of cancer cells. Protein kinase-C iota (PKC iota) is a member of the atypical PKC family and an important downstream mediator in the phosphoinositide-3-kinase (PI-3-kinase) pathway. PKC iota expression was found to be upregulated in a subset of breast cancers and breast cancer cell lines. Activation of the PI-3-kinase pathway by introduction of mutant, oncogenic PIK3CA into breast mammary epithelial cells increased both the expression and activation of PKC iota. In breast cancer cells lines overexpressing PKC iota, depletion of PKC iota increased the number of senescent cells, as assessed by senescence-associated beta-galactosidase, morphology and bromodeoxyuridine incorporation. This phenomenon was not restricted to breast cancer cells, as it was also seen in glioblastoma cells in which PKC iota is activated by loss of PTEN. Senescence occurred in the absence of a detectable DNA-damage response, was dependent on p21 and was enhanced by the aurora kinase inhibitor VX-680, suggesting that senescence is triggered by defects in mitosis. Depletion of PKCi had no effect on senescence in normal mammary epithelial cell lines. We conclude that PKC iota is overexpressed in a subset of cancers where it functions to suppress premature senescence. This function appears to be restricted to cancer cells and inhibition of PKC iota may therefore be an effective way to selectively activate premature senescence in cancer cells. Oncogene (2012) 31, 3584-3596; doi:10.1038/onc.2011.524; published online 28 November 2011