科研之友
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摘要
Retinoid X receptor alpha (RXR alpha) and its N-terminally truncated version, tRXR alpha, are widely implicated in cancer development and represent intriguing targets for cancer prevention and treatment. Successful manipulation of RXR alpha and tRXR alpha requires the identification of their modulators that could produce therapeutic effects. Here, we report that a class of nitrostyrene derivatives bind to RXR alpha by a unique mechanism, of which the nitro group of nitrostyrene derivatives and Cys432 of RXR alpha are required for binding. The binding results in the potent activation of Gal4-DBD-RXR alpha-LBD transactivation. However, the binding inhibits the transactivation of RXR alpha homodimer, which might be due to the distinct conformation of RXR alpha homodimer induced by these nitrostyrene derivatives. Two RXR alpha 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 TNF alpha/NF kappa B signaling pathway in a tRXR alpha-dependent manner. tRXR alpha promotes TNF alpha-induced NF-kappa B activation through its interaction with TRAF2 and enhances TNF alpha-induced ubiquitination of RIP1, which is strongly inhibited by nitrostyrene derivatives. The inhibition of TNF alpha-induced NF-kappa B activation results in the synergistic effect of the combination of nitrostyrene derivatives and TNF alpha on the induction of cancer cell apoptosis. Together, our results show a new class of RXR alpha modulators that induce apoptosis of cancer cells through their unique binding mode and new mechanism of action.
- 出版日期2015-5-15
- 单位厦门大学
