title: PKCη promotes senescence induced by oxidative stress and chemotherapy.
abstract: Senescence is characterized by permanent cell-cycle arrest despite continued viability and metabolic activity, in conjunction with the secretion of a complex mixture of extracellular proteins and soluble factors known as the senescence-associated secretory phenotype (SASP). Cellular senescence has been shown to prevent the proliferation of potentially tumorigenic cells, and is thus generally considered a tumor suppressive process. However, some SASP components may act as pro-tumorigenic mediators on premalignant cells in the microenvironment. A limited number of studies indicated that protein kinase C (PKC) has a role in senescence, with different isoforms having opposing effects. It is therefore important to elucidate the functional role of specific PKCs in senescence. Here we show that PKCη, an epithelial specific and anti-apoptotic kinase, promotes senescence induced by oxidative stress and DNA damage. We further demonstrate that PKCη promotes senescence through its ability to upregulate the expression of the cell cycle inhibitors p21(Cip1) and p27(Kip1) and enhance transcription and secretion of interleukin-6 (IL-6). Moreover, we demonstrate that PKCη creates a positive loop for reinforcing senescence by increasing the transcription of both IL-6 and IL-6 receptor, whereas the expression of IL-8 is specifically suppressed by PKCη. Thus, the presence/absence of PKCη modulates major components of SASP. Furthermore, we show that the human polymorphic variant of PKCη, 374I, that exhibits higher kinase activity in comparison to WT-374V, is also more effective in IL-6 secretion, p21(Cip1) expression and the promotion of senescence, further supporting a role for PKCη in senescence. As there is now considerable interest in senescence activation/elimination to control tumor progression, it is first crucial to reveal the molecular regulators of senescence. This will improve our ability to develop new strategies to harness senescence as a potential cancer therapy in the future.
authors.affiliation: The Shraga Segal Department of Microbiology Immunology and Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel.
authors.forename: U
authors.initials: U
authors.lastname: Zurgil
authors.affiliation: The Shraga Segal Department of Microbiology Immunology and Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Ben-Ari
authors.affiliation: The Shraga Segal Department of Microbiology Immunology and Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel.
authors.forename: K
authors.initials: K
authors.lastname: Atias
authors.affiliation: The Shraga Segal Department of Microbiology Immunology and Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel.
authors.forename: N
authors.initials: N
authors.lastname: Isakov
authors.affiliation: The Shraga Segal Department of Microbiology Immunology and Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Apte
authors.affiliation: The Shraga Segal Department of Microbiology Immunology and Genetics, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer Sheva 84105, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Livneh
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D019556:COS Cells; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics*; D002522:Chlorocebus aethiops; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics* / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D018384:Oxidative Stress; D010957:Plasmids; D011493:Protein Kinase C / Q000235:genetics* / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D019947:Receptors, Interleukin-6; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004317:Doxorubicin; C081975:protein kinase C eta; D011493:Protein Kinase C; D001616:beta-Galactosidase