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 p21Cip1 and p27Kip1 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, p21Cip1 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.

Downregulation of peroxiredoxin-3 by hydrophobic bile acid induces mitochondrial dysfunction and cellular senescence in human trophoblasts

“…The increased activity of senescence-associated β-galactosidase (SA-β-gal) is used as a biochemical marker for cellular senescence24. In our study, PRDX3-knockdown cells showed a significantly higher number of SA-β-gal stained cells compared with sh-scr control cells at basal level (Fig.…”

“…Accumulation of oxidative stress and cell-cycle arrest would result in cellular senescence2324. The increased activity of senescence-associated β-galactosidase (SA-β-gal) is used as a biochemical marker for cellular senescence24.…”

“…Thus, the function of PRDX3 in cell growth regulation was dependent on cellular background43. Accumulation of oxidative stress and cell cycle arrest would result in cellular senescence2324. Until now, the role of PRDX3 in placental trophoblast cells senescence has not been reported.…”

Epigenetic signatures of gestational diabetes mellitus on cord blood methylation

“…PRKCH , which is hypomethylated in GDM offspring, belongs to the protein kinase C family that is involved in diverse cellular signaling pathways. It can promote cellular senescence through transcriptional upregulation of cell cycle inhibitors p21 and p27 [56]. PRKCH variants have been associated with early-onset obesity [48] and increased stroke risk [45, 46].…”

Protein kinase C: perfectly balanced

“…In vitro kinase assays reveal that the mutation enhances the catalytic activity of PKC, as assessed by increased autophosphorylation and substrate phosphorylation (Kubo et al 2007; Zurgil et al 2014). Assuming autoinhibitory constraints are unchanged (as is the case for the activity-enhancing PKCα M489V variant in Alzheimer’s disease), the enhanced catalytic activity would serve as an effective mechanism to allow enhanced activity without compromising the stability of the mutant.…”