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Repression of cancer cell senescence by PKCι

Oncogene volume 31, pages 3584–3596 (2012)Cite this article

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Abstract

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-Cι (PKCι) is a member of the atypical PKC family and an important downstream mediator in the phosphoinositide-3-kinase (PI-3-kinase) pathway. PKCι 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 PKCι. In breast cancer cells lines overexpressing PKCι, depletion of PKCι increased the number of senescent cells, as assessed by senescence-associated β-galactosidase, morphology and bromodeoxyuridine incorporation. This phenomenon was not restricted to breast cancer cells, as it was also seen in glioblastoma cells in which PKCι 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 PKCι had no effect on senescence in normal mammary epithelial cell lines. We conclude that PKCι 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 PKCι may therefore be an effective way to selectively activate premature senescence in cancer cells.

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Acknowledgements

This work was supported by grants from the Canadian Institutes of Health Research and the Ottawa Regional Cancer Foundation (to IAJL). JP was supported by a Canadian Institutes of Health Research Banting and Best MSc Scholarship. IR is supported by an Ontario Graduate Scholarship in Science and Technology. We thank Sharon Rowan and Mara Coiciu for their work on the initial characterization of PKCι activation in breast cancer cells.

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  1. J A Paget and I J Restall: These authors contributed equally to this work.

Authors and Affiliations

  1. Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

    J A Paget, I J Restall, M Daneshmand, J A Mersereau, M A Simard, D A E Parolin, S J Lavictoire & I A J Lorimer

  2. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada

    J A Paget, I J Restall & I A J Lorimer

  3. Department of Pathology, Ottawa Hospital, Ottawa, Ontario, Canada

    M S Amin & S Islam

  4. Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada

    I A J Lorimer

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Paget, J., Restall, I., Daneshmand, M. et al. Repression of cancer cell senescence by PKCι. Oncogene 31, 3584–3596 (2012). https://doi.org/10.1038/onc.2011.524

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