Antagonist Effect of Triptolide on AKT Activation by Truncated Retinoid X Receptor-alpha
- 生物医学－已发表论文 
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.