Cellular senescence refers to the essentially irreversible growth arrest that occurs when cells that can divide encounter oncogenic stress. Most division-competent cells, including some tumor cells, can undergo senescence when appropriately stimulated, senescent cells are characterized by secretion of cytokines (secretome) and express of senescence markers such as p16 and p21. PKC members have been shown to play a role in senescence activity. Here we found a role in senescence for the polymorphic substitution of valine (374V) to isoleucine in the kinase domain of PKCη (PKCη -374I). This polymorphism was previously reported to increases the susceptibility for
Rheumatoid Arthritis (RA) and stroke in the Japanese population. The V374I substitution results in higher levels of kinase activity. Over-expression of PKCη 374V and 374I in MCF-7 cells enhanced the secretion of IL-6. In the presence of oxidative stress (H2O2), over-expressed PKCη 374I induced significantly higher IL-6 production compared to both untreated control and to 374V treated cells. Nonetheless, PKCη 374V also showed significantly higher IL-6 production compared to untreated cells, suggesting that PKCη itself is involved in IL-6 secretion. We found that over-
expressed PKCη 374V that was exposed to oxidative stress, expressed higher levels of senescence associated proteins (p16, p21) compared to the control cells. The levels of senescence associated proteins in MCF-7 over-expressed PKCη 374I were even higher. Our previous findings suggest that PKCη-374I/374V are involved in cancer cells protection against cell death. Here we demonstrate that this might involve the activation of the senescence mechanism. Specifically it seems that PKCη has a role in IL-6 production and up-regulation of other senescence associated markers. The fact that more senescent cells were induced by PKCη is in correlation with our data that fewer cells were able to proliferate from after induction of senescence in scrambled-control cells compared to the PKCη-knocked down cells. Taken together, our data
suggest that PKCη is involved in establishing the senescence phenotype under H2O2
stress conditions.
