Abstract 464: Cell death and senescence: Role of protein kinase C in promoting senescence

Abstract

Abstract Senescence is characterized by permanent cell cycle arrest and loss of proliferative capacity, despite continued viability and metabolic activity. Senescent cells undergo massive genome modulation including induction of the senescence-associated secretory phenotype (SAPS). Components of SASP can implement cell cycle arrest or recruit the immune system to clear senescent cells, thus contributing to tumor suppression. However, some secreted pro-inflammation molecules, act as pro-tumorigenic agents contributing to tumor progression, suggesting that elimination of senescent cells could be beneficial. Very few studies showed a role for PKC in senescence. Here we show that PKCeta, an epithelial specific and anti-apoptotic kinase (epithelia is the origin of about 90% of human tumors), promotes senescence induced by oxidative stress and DNA damage. Using PKCeta-knockdown breast adenocarcinoma MCF-7 cells we show that PKCeta promotes senescence induced by oxidative stress and DNA damage via its ability to upregulate the expression of the cell cycle inhibitors p21Cip1 and p27Kip1 and to modulate transcription of major components of SASP such as IL-6 and IL-8. Moreover, we demonstrate that PKCeta creates a positive loop for reinforcing senescence by increasing the transcription of both IL-6 and IL-6 receptor. Thus, the expression of PKCeta modulates major components of SASP. Furthermore, our studies demonstrate that PKCeta interferes with γH2AX phosphorylation, which mark DNA double-strand breaks for repair. The phosphorylation of γH2AX may reflect the extent of DNA breaks but also the cellular response to DNA damage. Our experiments suggest that the response to DNA damage (repair processes) was more efficient in PKCeta-knockdown cells. The phosphorylation on ATM and Chk2 was also lower in PKCeta expressing cells. Revealing the molecular regulators of senescence will improve our ability to develop new therapeutic strategies for clearing tumor cells. Our studies showing a role for PKCeta in senescence could identify PKCeta and/or its activated signaling cascades as targets for intervention senescence induction. Since PKCeta is highly expressed in epithelia that are the origin of about 90% of human tumors, this may provide critical inhibitors as therapeutic adjuvants for different types of carcinomas. Citation Format: Etta Livneh, Assaf Ben Ari, Udi Zurgil. Cell death and senescence: Role of protein kinase C in promoting senescence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 464.