Antagonist effect of triptolide on AKT activation by truncated retinoid X receptor-alpha.

Abstract

BACKGROUND:

Retinoid X receptor-alpha (RXRα) is a key member of the nuclear receptor superfamily. We recently demonstrated that proteolytic cleavage of RXRα resulted in production of a truncated product, tRXRα, which promotes cancer cell survival by activating phosphatidylinositol-3-OH kinase (PI3K)/AKT pathway. However, how the tRXRα-mediated signaling pathway in cancer cells is regulated remains elusive.

METHODOLOGY/PRINCIPAL FINDINGS:

We screened a natural product library for tRXRα targeting leads and identified that triptolide, an active component isolated from traditional Chinese herb Trypterygium wilfordii Hook F, could modulate tRXRα-mediated cancer cell survival pathway in vitro and in animals. Our results reveal that triptolide strongly induces cancer cell apoptosis dependent on intracellular tRXRα expression levels, demonstrating that tRXRα serves as an important intracellular target of triptolide. We show that triptolide selectively induces tRXRα degradation and inhibits tRXRα-dependent AKT activity without affecting the full-length RXRα. 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 tRXRα degradation and AKT activity are only reversed by p38 siRNA and p38 inhibitor. In addition, the p38 inhibitor potently inhibits tRXRα interaction with p85α leading to AKT inactivation. Our results demonstrate an interesting novel signaling interplay between p38 and AKT through tRXRα mediation. We finally show that targeting tRXRα by triptolide strongly activates TNFα death signaling and enhances the anticancer activity of other chemotherapies.

CONCLUSIONS/SIGNIFICANCE:

Our results identify triptolide as a new xenobiotic regulator of the tRXRα-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.

• Authors: Na Lu, Jinxing Liu, Jie Liu, Chunyun Zhang, Fuquan Jiang, Hua Wu, Liqun Chen, Wenjun Zeng, Xihua Cao, Tingdong Yan, Guanghui Wang, Hu Zhou, Bingzhen Lin, Xiaomei Yan, Xiao-kun Zhang, Jin-Zhang Zeng
• Journal: PloS one (PLoS One) Vol. 7 Issue 4 Pg. e35722 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 22545132 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Alkylating
• Diterpenes
• Drugs, Chinese Herbal
• Epoxy Compounds
• Phenanthrenes
• Retinoid X Receptor alpha
• Tumor Necrosis Factor-alpha
• triptolide
• Proto-Oncogene Proteins c-akt
• Caspase 8
• Caspase 9

Topics

• Animals
• Antineoplastic Agents, Alkylating (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Caspase 8 (metabolism)
• Caspase 9 (metabolism)
• Cell Line
• Cell Line, Tumor
• Diterpenes (pharmacology, therapeutic use)
• Drugs, Chinese Herbal (pharmacology, therapeutic use)
• Enzyme Activation (drug effects)
• Epoxy Compounds (pharmacology, therapeutic use)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasms (drug therapy, enzymology, genetics, metabolism)
• Phenanthrenes (pharmacology, therapeutic use)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Retinoid X Receptor alpha (genetics, metabolism)
• Signal Transduction (drug effects)
• Tumor Necrosis Factor-alpha (metabolism)