Prostaglandin E2 prevents radiotherapy-induced alopecia by attenuating transit amplifying cell apoptosis through promoting G1 arrest

Abstract

Growing hair follicles (HFs) harbor actively dividing transit amplifying cells (TACs), rendering them highly sensitive to radiotherapy (RT). Clinically, there is still a lack of effective treatment for radiotherapy-induced alopecia (RIA). We aimed to dissect the effect and mechanism of local prostaglandin E2 (PGE2) pretreatment in RIA prevention. We found that PGE2 pretreatment reduced RIA by preventing premature termination of anagen through enhancing HF self-repair. Mechanistically, PGE2 did not activate HF stem cells, but preserved more TACs for regenerative attempts. Pretreatment of PGE2 lessened radiosensitivity of TACs by transiently arresting them in the G1 phase, thereby reducing TAC apoptosis and mitigating HF dystrophy. The preservation of more TACs accelerated HF self-repair and bypassed RT-induced premature catagen entry. Promoting G1 arrest by systemic administration of palbociclib isethionate (PD0332991), a CDK4/6 inhibitor, offered a similar protective effect against RT. Therefore, PGE2 protects HF TACs from RT by transiently inducing G1 arrest, and the regeneration of HF structures lost from RT is accelerated to resume anagen growth, thus bypassing the long downtime of hair loss. PGE2 has the potential to be repurposed as a preventive treatment for RIA.