Activation of epidermal growth factor receptor signaling mediates cellular senescence induced by certain pro‐inflammatory cytokines. Issue 5 (22nd April 2020) - Shang, Dongsheng
Abstract: It is well established that inflammation in the body promotes organism aging, and recent studies have attributed a similar effect to senescent cells. Considering that certain pro‐inflammatory cytokines can induce cellular senescence, systematically evaluating the effects of pro‐inflammatory cytokines in cellular senescence is an important and urgent scientific problem, especially given the ongoing surge in aging human populations. Treating IMR90 cells and HUVECs with pro‐inflammatory cytokines identified six factors able to efficiently induce cellular senescence. Of these senescence‐inducing cytokines, the activity of five (namely IL‐1β, IL‐13, MCP‐2, MIP‐3α, and SDF‐1α) was significantly inhibited by treatment with cetuximab (an antibody targeting epidermal growth factor receptor [EGFR]), gefitinib (a small molecule inhibitor of EGFR), and EGFR knockdown. In addition, treatment with one of the senescence‐inducing cytokines, SDF‐1α, significantly increased the phosphorylation levels of EGFR, as well as Erk1/2. These results suggested that pro‐inflammatory cytokines induce cellular senescence by activating EGFR signaling. Next, we found that EGF treatment could also induce cellular senescence of IMR90 cells and HUVECs. Mechanically, EGF induced cellular senescence via excessive activation of Ras and the Ras‐BRaf‐Erk1/2 signaling axis. Moreover, EGFR activation induced IMR90 cells to secrete certain senescence‐associated secretory phenotype factors (IL‐8 and MMP‐3). In summary, we report that certain pro‐inflammatory cytokines induce cellular senescence through activation of the EGFR‐Ras signaling pathway. Our study thus offers new insight into a long‐ignored mechanism by which EGFR could regulate cellular senescence and suggests that growth signals themselves may catalyze aging under certain conditions. Abstract : Pro‐inflammatory cytokines were screened, and five of these cytokines were identified to induce cellular senescence by activating EGFR‐Ras signaling pathway, a long‐ignored mechanism by which EGFR could regulate cellular senescence. These results suggest that growth signals themselves may catalyze aging under certain conditions.