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PKC? 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 PKC?, an epithelial specific and anti-apoptotic kinase, promotes senescence induced by oxidative stress and DNA damage. We further demonstrate that PKC? 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 PKC? 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 PKC?. Thus, the presence/absence of PKC? modulates major components of SASP. Furthermore, we show that the human polymorphic variant of PKC?, 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 PKC? 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.

SUBMITTER: Zurgil U

PROVIDER: S-EPMC4260739 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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PKCη promotes senescence induced by oxidative stress and chemotherapy.

Zurgil U U Ben-Ari A A Atias K K Isakov N N Apte R R Livneh E E

Cell death & disease 20141120

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 mediator ...[more]

PMID: 25412309

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Project description:BackgroundCell senescence is central to a large body of age related pathology, and accordingly, cardiomyocytes senescence is involved in many age related cardiovascular diseases. In consideration of that, delaying cardiomyocytes senescence is of great importance to control clinical cardiovascular diseases. Previous study indicated that bradykinin (BK) protected endothelial cells from senescence induced by oxidative stress. However, the effects of bradykinin on cardiomyocytes senescence remain to be elucidated. In this study, we investigated the effect of bradykinin on H2O2-induced H9C2 cells senescence.Methods and resultsBradykinin pretreatment decreased the senescence induced by H2O2 in cultured H9C2 cells in a dose dependent manner. Interestingly, 1 nmol/L of BK almost completely inhibited the increase in senescent cell number and p21 expression induced by H2O2. Since H2O2 induces senescence through superoxide-induced DNA damage, we also observed the DNA damage by comet assay, and BK markedly reduced DNA damage induced by H2O2, and moreover, BK treatment significantly prevented reactive oxygen species (ROS) production in H9C2 cells treated with H2O2. Importantly, when co-incubated with bradykinin B2 receptor antagonist HOE-140 or eNOS inhibitor N-methyl-L-arginine acetate salt (L-NAME), the protective effects of bradykinin on H9C2 senescence were totally blocked. Furthermore, BK administration significantly prevented the increase in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity characterized by increased ROS generation and gp91 expression and increased translocation of p47 and p67 to the membrane and the decrease in superoxide dismutase (SOD) activity and expression induced by H2O2 in H9C2 cells, which was dependent on BK B2 receptor mediated nitric oxide (NO) release.ConclusionsBradykinin, acting through BK B2 receptor induced NO release, upregulated antioxidant Cu/Zn-SOD and Mn-SOD activity and expression while downregulating NADPH oxidase activity and subsequently inhibited ROS production, and finally protected against cardiomyocytes senescence induced by oxidative stress.

Project description:Both environmental exposure to vanadium pentoxide (V2O5, V+5 for its ionic counterparts) and fibroblast senescence are associated with pulmonary fibrosis, but whether V+5 causes fibroblast senescence remains unknown. We found in a dose-response study that 2-40 μM V+5 caused human lung fibroblasts (HLF) senescence with increased senescence-associated β-galactosidase activity and p16 expression, while cell death occurred at higher concentration (LC50, 82 μM V+5). Notably, measures of reactive oxygen species (ROS) production with fluorescence probes showed no association of ROS with V+5-dependent senescence. Preloading catalase (polyethylene-conjugated), a H2O2 scavenger, did not alleviate the cellular senescence induced by V+5. Analyses of the cellular glutathione (GSH) system showed that V+5 oxidized GSH, increased GSH biosynthesis, stimulated cellular GSH efflux and increased protein S-glutathionylation, and addition of N-acetyl cysteine inhibited V+5-elevated p16 expression, suggesting that thiol oxidation mediates V+5-caused senescence. Moreover, strong correlations between GSSG/GSH redox potential (Eh), protein S-glutathionylation, and cellular senescence (R2 > 0.99, p < 0.05) were present in V+5-treated cells. Studies with cell-free and enzyme-free solutions showed that V+5 directly oxidized GSH with formation of V+4 and GSSG in the absence of O2. Analyses of V+5 and V+4 in HLF and culture media showed that V+5 was reduced to V+4 in cells and that a stable V+4/V+5 ratio was rapidly achieved in extracellular media, indicating ongoing release of V+4 and reoxidation to V+5. Together, the results show that V+5-dependent fibroblast senescence is associated with a cellular/extracellular redox cycling mechanism involving the GSH system and occurring under conditions that do not cause cell death. These results establish a mechanism by which environmental vanadium from food, dietary supplements or drinking water, can cause or contribute to lung fibrosis in the absence of high-level occupational exposures and cytotoxic cell death.

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PKC? promotes senescence induced by oxidative stress and chemotherapy.

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PKCη promotes senescence induced by oxidative stress and chemotherapy.

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