Nitrostyrene Derivatives Act as RXRα Ligands to Inhibit TNFα Activation of NF-κB.

Abstract

Retinoid X receptor alpha (RXRα) and its N-terminally truncated version, tRXRα, are widely implicated in cancer development and represent intriguing targets for cancer prevention and treatment. Successful manipulation of RXRα and tRXRα requires the identification of their modulators that could produce therapeutic effects. Here, we report that a class of nitrostyrene derivatives bind to RXRα by a unique mechanism, of which the nitro group of nitrostyrene derivatives and Cys432 of RXRα are required for binding. The binding results in the potent activation of Gal4-DBD-RXRα-LBD transactivation. However, the binding inhibits the transactivation of RXRα homodimer, which might be due to the distinct conformation of RXRα homodimer induced by these nitrostyrene derivatives. Two RXRα point mutants with Cys432 substituted with Tyr and Trp, respectively, could mimic the bindings of two nitrostyrene derivatives and have the ability of autotransactivation. In studying the functional consequences of the binding, we show that these nitrostyrene derivatives could potently inhibit the TNFα/NFκB signaling pathway in a tRXRα-dependent manner. tRXRα promotes TNFα-induced NF-κB activation through its interaction with TRAF2 and enhances TNFα-induced ubiquitination of RIP1, which is strongly inhibited by nitrostyrene derivatives. The inhibition of TNFα-induced NF-κB activation results in the synergistic effect of the combination of nitrostyrene derivatives and TNFα on the induction of cancer cell apoptosis. Together, our results show a new class of RXRα modulators that induce apoptosis of cancer cells through their unique binding mode and new mechanism of action.

• Authors: Zhiping Zeng, Zhe Sun, Mingfeng Huang, Weidong Zhang, Jie Liu, Liqun Chen, Fan Chen, Yuqi Zhou, Jiacheng Lin, Fengyu Huang, Lin Xu, Zixing Zhuang, Shangjie Guo, Gulimiran Alitongbieke, Guobin Xie, Yang Xu, Bingzhen Lin, Xihua Cao, Ying Su, Xiao-Kun Zhang, Hu Zhou
• Journal: Cancer research (Cancer Res) Vol. 75 Issue 10 Pg. 2049-60 (May 15 2015) ISSN: 1538-7445 [Electronic] United States
• PMID: 25795708 (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.)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• (E)-1-(2-nitrovinyl)naphthalene
• (E)-9-(2-nitrovinyl)anthracene
• Anthracenes
• Antineoplastic Agents
• NF-kappa B
• Naphthalenes
• Retinoid X Receptor alpha
• Styrenes
• TNF Receptor-Associated Factor 2
• TNF protein, human
• Tumor Necrosis Factor-alpha

Topics

• Animals
• Anthracenes (pharmacology)
• Antineoplastic Agents (pharmacology)
• Apoptosis
• HEK293 Cells
• Humans
• MCF-7 Cells
• Mice, Inbred BALB C
• Mice, Nude
• NF-kappa B (genetics, metabolism)
• Naphthalenes (pharmacology)
• Protein Binding
• Retinoid X Receptor alpha (agonists, metabolism)
• Signal Transduction
• Styrenes (pharmacology)
• TNF Receptor-Associated Factor 2 (metabolism)
• Transcriptional Activation
• Tumor Necrosis Factor-alpha (physiology)
• Ubiquitination
• Xenograft Model Antitumor Assays