title: Repression of cancer cell senescence by PKCι.
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.
authors: Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
authors: J A
authors: JA
authors: Paget
authors: I J
authors: IJ
authors: Restall
authors: M
authors: M
authors: Daneshmand
authors: J A
authors: JA
authors: Mersereau
authors: M A
authors: MA
authors: Simard
authors: D A E
authors: DA
authors: Parolin
authors: S J
authors: SJ
authors: Lavictoire
authors: M S
authors: MS
authors: Amin
authors: S
authors: S
authors: Islam
authors: I A J
authors: IA
authors: Lorimer
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology*; D058534:Class I Phosphatidylinositol 3-Kinases; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005260:Female; D005909:Glioblastoma / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000096:biosynthesis*; D014162:Transfection; D015854:Up-Regulation; D001616:beta-Galactosidase / Q000032:analysis; D000099293:Protein Kinase C-lambda; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
chemical_list: D000970:Antineoplastic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D010879:Piperazines; D011493:Protein Kinase C; D001616:beta-Galactosidase; D000099293:Protein Kinase C-lambda; C493956:CDKN1A protein, human; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines; C484760:PIK3CA protein, human