부산대학교 도서관

Background Retinoid X receptor-alpha (RXR[alpha]) is a key member of the nuclear receptor superfamily. We recently demonstrated that proteolytic cleavage of RXR[alpha] resulted in production of a truncated product, tRXR[alpha], which promotes cancer cell survival by activating phosphatidylinositol-3-OH kinase (PI3K)/AKT pathway. However, how the tRXR[alpha]-mediated signaling pathway in cancer cells is regulated remains elusive. Methodology/Principal Findings We screened a natural product library for tRXR[alpha] targeting leads and identified that triptolide, an active component isolated from traditional Chinese herb Trypterygium wilfordii Hook F, could modulate tRXR[alpha]-mediated cancer cell survival pathway in vitro and in animals. Our results reveal that triptolide strongly induces cancer cell apoptosis dependent on intracellular tRXR[alpha] expression levels, demonstrating that tRXR[alpha] serves as an important intracellular target of triptolide. We show that triptolide selectively induces tRXR[alpha] degradation and inhibits tRXR[alpha]-dependent AKT activity without affecting the full-length RXR[alpha]. Interestingly, such effects of triptolide are due to its activation of p38. Although triptolide also activates Erk1/2 and MAPK pathways, the effects of triptolide on tRXR[alpha] degradation and AKT activity are only reversed by p38 siRNA and p38 inhibitor. In addition, the p38 inhibitor potently inhibits tRXR[alpha] interaction with p85[alpha] leading to AKT inactivation. Our results demonstrate an interesting novel signaling interplay between p38 and AKT through tRXR[alpha] mediation. We finally show that targeting tRXR[alpha] by triptolide strongly activates TNF[alpha] death signaling and enhances the anticancer activity of other chemotherapies Conclusions/Significance Our results identify triptolide as a new xenobiotic regulator of the tRXR[alpha]-dependent survival pathway and provide new insight into the mechanism by which triptolide acts to induce apoptosis of cancer cells. Triptolide represents one of the most promising therapeutic leads of natural products of traditional Chinese medicine with unfortunate side-effects. Our findings will offer new strategies to develop improved triptolide analogs for cancer therapy.
Author(s): Na Lu 1 , Jinxing Liu 1 , Jie Liu 1 , Chunyun Zhang 1 , Fuquan Jiang 1 , Hua Wu 1 , Liqun Chen 1 , Wenjun [...]