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Nitrostyrene Derivatives Act as RXR? Ligands to Inhibit TNF? Activation of NF-?B.

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

SUBMITTER: Zeng Z

PROVIDER: S-EPMC4433622 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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

Zeng Zhiping Z Sun Zhe Z Huang Mingfeng M Zhang Weidong W Liu Jie J Chen Liqun L Chen Fan F Zhou Yuqi Y Lin Jiacheng J Huang Fengyu F Xu Lin L Zhuang Zixing Z Guo Shangjie S Alitongbieke Gulimiran G Xie Guobin G Xu Yang Y Lin Bingzhen B Cao Xihua X Su Ying Y Zhang Xiao-Kun XK Zhou Hu H

Cancer research 20150320 10

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 require ...[more]

PMID: 25795708

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Project description:The sodium-iodide symporter (NIS) mediates transport of iodide across the basolateral membrane of thyroid cells. NIS expression in thyroid cancer (TC) cells allows the use of radioactive iodine (RAI) as a diagnostic and therapeutic tool, being RAI therapy the systemic treatment of choice for metastatic disease. Still, a significant proportion of patients with advanced TC lose the ability to respond to RAI therapy and no effective alternative therapies are available. Defective NIS expression is the main reason for impaired iodide uptake in TC and NIS downregulation has been associated with several pathways linked to malignant transformation. NF-κB signaling is one of the pathways associated with TC. Interestingly, NIS expression can be negatively regulated by TNF-α, a bona fide activator of NF-κB with a central role in thyroid autoimmunity. This prompted us to clarify NF-kB's role in this process. We confirmed that TNF-α leads to downregulation of TSH-induced NIS expression in non-neoplastic thyroid follicular cell-derived models. Notably, a similar effect was observed when NF-κB activation was triggered independently of ligand-receptor specificity, using phorbol-myristate-acetate (PMA). TNF-α and PMA downregulation of NIS expression was reverted when NF-κB-dependent transcription was blocked, demonstrating the requirement for NF-kB activity. Additionally, TNF-α and PMA were shown to have a negative impact on TSH-induced iodide uptake, consistent with the observed transcriptional downregulation of NIS. Our data support the involvement of NF-κB-directed transcription in the modulation of NIS expression, where up- or down-regulation of NIS depends on the combined output to NF-κB of several converging pathways. A better understanding of the mechanisms underlying NIS expression in the context of normal thyroid physiology may guide the development of pharmacological strategies to increase the efficiency of iodide uptake. Such strategies would be extremely useful in improving the response to RAI therapy in refractory-TC.

Dataset Information

Nitrostyrene Derivatives Act as RXR? Ligands to Inhibit TNF? Activation of NF-?B.

Publications

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

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