Targeting truncated retinoid X receptor-α by CF31 induces TNF-α-dependent apoptosis.

Abstract

A truncated version of retinoid X receptor-α, tRXR-α, promotes cancer cell survival by activating the phosphoinositide 3-kinase (PI3K)/AKT pathway. However, targeting the tRXR-α-mediated survival pathway for cancer treatment remains to be explored. We report here our identification of a new natural product molecule, CF31, a xanthone isolated from Cratoxylum formosum ssp. pruniflorum, and the biologic evaluation of its regulation of the tRXR-α-mediated PI3K/AKT pathway. CF31 binds RXR-α and its binding results in inhibition of RXR-α transactivation. Through RXR-α mutational analysis and computational studies, we show that Arg316 of RXR-α, known to form salt bridges with certain RXR-α ligands, such as 9-cis-retinoic acid (9-cis-RA), is not required for the antagonist effect of CF31, showing a distinct binding mode. Evaluation of several CF31 analogs suggests that the antagonist effect is mainly attributed to an interference with Leu451 of helix H12 in RXR-α. CF31 is a potent inhibitor of AKT activation in various cancer cell lines. When combined with TNF-α, it suppresses TNF-α activation of AKT by inhibiting TNF-α-induced tRXR-α interaction with the p85α regulatory subunit of PI3K. CF31 inhibition of TNF-α activation of AKT also results in TNF-α-dependent activation of caspase-8 and apoptosis. Together, our results show that CF31 is an effective converter of TNF-α signaling from survival to death by targeting tRXR-α in a unique mode and suggest that identification of a natural product that targets an RXR-mediated cell survival pathway that regulates PI3K/AKT may offer a new therapeutic strategy to kill cancer cells.

• Authors: Guang-Hui Wang, Fu-Quan Jiang, Ying-Hui Duan, Zhi-Ping Zeng, Fan Chen, Yi Dai, Jie-Bo Chen, Jin-Xing Liu, Jie Liu, Hu Zhou, Hai-Feng Chen, Jin-Zhang Zeng, Ying Su, Xin-Sheng Yao, Xiao-Kun Zhang
• Journal: Cancer research (Cancer Res) Vol. 73 Issue 1 Pg. 307-18 (Jan 01 2013) ISSN: 1538-7445 [Electronic] United States
• PMID: 23151904 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• CF31 xanthone
• Retinoid X Receptor alpha
• Tumor Necrosis Factor-alpha
• Xanthones

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, physiology)
• Blotting, Western
• Clusiaceae (chemistry)
• Humans
• Immunoprecipitation
• Microscopy, Fluorescence
• Models, Molecular
• Phytotherapy (methods)
• Plant Stems (chemistry)
• Retinoid X Receptor alpha (antagonists & inhibitors)
• Signal Transduction (drug effects)
• Tumor Necrosis Factor-alpha (metabolism)
• Xanthones (chemistry, pharmacology)