Celastrol Strongly Inhibits Proliferation, Migration and Cancer Stem Cell Properties Through Suppression of Pin1 in Ovarian Cancer Cells

Ovarian cancer is one of the most serious diseases worldwide and the fifth-most common cancer among women. Celastrol, extracted from Thunder God Vine, exerts anti-cancer effects on various cancers; however, the mechanism underlying these anti-cancer effects in ovarian cancer needs further investigation. Herein, we investigated the anti-cancer efficacy of celastrol and its underlying mechanism in human ovarian cancer cell lines A2780, OVCAR3, and SKOV3. Celastrol significantly suppressed cell proliferation and migration in a dose-dependent manner. Celastrol resulted in a G2/M cell cycle arrest, accompanied with the down-regulation of Cyclin D1, CDK2, and CDK4. Celastrol induced apoptosis primarily via up-regulation of caspase-3, caspase-8, and Bax, and down-regulation of Bcl-2. Celastrol treatment inhibited the expression of stem cell marker CD44, Nanog, Klf4, and Oct4, and reduced a portion of the CD44CD24 cell population. To further understand the cancer therapeutic target, we assessed the effect of celastrol on expression of Pin1, which is reportedly overexpressed in many human cancers and activates more than 40 oncogenes or inactivates more than 20 tumor suppressor genes. We report that celastrol particularly suppressed Pin1 expression, thereby inhibiting Akt, STAT3, P38, JNK, P65, and IL-6 expression. Taken together, these findings indicate that celastrol is a potential therapeutic agent for ovarian cancer in humans via inhibition of Pin1 expression.