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	Antagonist Effect of Triptolide on AKT Activation by Truncated Retinoid X Receptor-alpha
	Lu, Na ; Liu, Jinxing ; Liu, Jie ; Zhang, Chunyun ; Jiang, Fuquan ; Wu, Hua ; Chen, Liqun ; Zeng, Wenjun ; Cao, Xihua ; Yan, Tingdong ; Wang, Guanghui ; Zhou, Hu ; Lin, Bingzhen ; Yan, Xiaomei ; Zhang, Xiao-kun ; Zhang XK(张晓坤) ; Zeng, Jin-Zhang ; Ceng JZ(曾锦章)
	2012-04-24
关键词	HUMAN HEPATOCELLULAR-CARCINOMA KAPPA-B ACTIVATION L-TYPE PROTEASE RXR-ALPHA CANCER-CELLS INDUCED APOPTOSIS TRIPTERYGIUM-WILFORDII 9-CIS-RETINOIC ACID SERINE-260 IMPAIRS EPITHELIAL-CELLS
英文摘要	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.; National Natural Science Foundation of China [NSFC: 30971445, 90913015, 91129302]; NSFC/Hong Kong Research Grants Council [NSFC/RGC: 30931160431/N_HKU 735/09]; Natural Science Foundation of Fujian Province [2009J01198]
语种	英语
出版者	PUBLIC LIBRARY SCIENCE
内容类型	期刊论文
源URL	[http://dx.doi.org/10.1371/journal.pone.0035722]
专题	生物医学－已发表论文
推荐引用方式 GB/T 7714	Lu, Na,Liu, Jinxing,Liu, Jie,et al. Antagonist Effect of Triptolide on AKT Activation by Truncated Retinoid X Receptor-alpha[J],2012.
APA	Lu, Na.,Liu, Jinxing.,Liu, Jie.,Zhang, Chunyun.,Jiang, Fuquan.,...&曾锦章.(2012).Antagonist Effect of Triptolide on AKT Activation by Truncated Retinoid X Receptor-alpha..
MLA	Lu, Na,et al."Antagonist Effect of Triptolide on AKT Activation by Truncated Retinoid X Receptor-alpha".(2012).

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