Stress‐activated cellular senescence as a mechanism of melanocytes degeneration in vitiligo

Abstract

Several studies show evidence of an alterated redox status and an increased susceptibility of vitiligo cells to pro‐oxidant agents, supporting the idea that an imbalance of the cellular redox status might be the pathogenic mechanism in vitiligo. In order to study intracellular pathways involved in stress‐dependent vitiligo cell damage, we focused on cAMP/PKA/CREB and mitogen activated protein kinases (MAPK)‐dependent signal transduction. We found correlation between intrinsic oxidative stress, activation MAPK and p53, hyperphosphorylation of CREB and increased cholesterol levels. Notably, these long‐term effects of subcytotoxic oxidative stress are also biomarkers of premature cellular senescence. Consistent with this, vitiligo cells showed a significant increase in p16 that did not correlate with the chronological age of the donors. Chronic stimulation of MAPK and downstream inhibition of cyclin‐dependent kinases in the presence of elevated levels of cyclinD1 suggest that vitiligo melanocytes are prone to entering a hypermitogenic cell cycle arrest. Accordingly, vitiligo cells displayed attenuated responses to mitogens. Moreover, vitiligo melanocytes produced biologically active proteins among the senescence‐associated secretory phenotype, such as MMP3, Cox‐2, IGFBPs. Together, these data argue for a pathologic predisposition of vitiligo cells to stress‐induced premature senescence.