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Protein & Cell

ISSN 1674-800X

ISSN 1674-8018(Online)

CN 11-5886/Q

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Protein Cell    2015, Vol. 6 Issue (9) : 654-666    https://doi.org/10.1007/s13238-015-0178-9
RESEARCH ARTICLE
NSC-640358 acts as RXRα ligand to promote TNFα-mediated apoptosis of cancer cell
Fan Chen1,2,Jiebo Chen1,Jiacheng Lin1,Anton V. Cheltsov3,Lin Xu1,Ya Chen4,Zhiping Zeng1,Liqun Chen1,Mingfeng Huang1,Mengjie Hu1,Xiaohong Ye1,Yuqi Zhou1,Guanghui Wang1,Ying Su1,4,Long Zhang5,Fangfang Zhou6,Xiao-kun Zhang1,4,*(),Hu Zhou1,*()
1. School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China
2. School of Biological Science and Biotechnology, Minnan Normal University, Zhangzhou 363000, China
3. Q-MOL LLC, San Diego, CA 92105, USA
4. Cancer Center, Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA
5. Life Science Institute, Zhejiang University, Hangzhou 310058, China
6. Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China
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Abstract

Retinoid X receptor α (RXRα) and its N-terminally truncated version tRXRα play important roles in tumorigenesis, while some RXRα ligands possess potent anticancer activities by targeting and modulating the tumorigenic effects of RXRα and tRXRα. Here we describe NSC-640358 (N-6), a thiazolyl-pyrazole derived compound, acts as a selective RXRα ligand to promote TNFα-mediated apoptosis of cancer cell. N-6 binds to RXRα and inhibits the transactivation of RXRα homodimer and RXRα/TR3 heterodimer. Using mutational analysis and computational study, we determine that Arg316 in RXRα, essential for 9-cis-retinoic acid binding and activating RXRα transactivation, is not required for antagonist effects of N-6, whereas Trp305 and Phe313 are crucial for N-6 binding to RXRα by forming extra π–π stacking interactions with N-6, indicating a distinct RXRα binding mode of N-6. N-6 inhibits TR3-stimulated transactivation of Gal4-DBD-RXRα-LBD by binding to the ligand binding pocket of RXRα-LBD, suggesting a strategy to regulate TR3 activity indirectly by using small molecules to target its interacting partner RXRα. For its physiological activities, we show that N-6 strongly inhibits tumor necrosis factor α (TNFα)-induced AKT activation and stimulates TNFα-mediated apoptosis in cancer cells in an RXRα/tRXRα dependent manner. The inhibition of TNFα-induced tRXRα/p85α complex formation by N-6 implies that N-6 targets tRXRα to inhibit TNFα-induced AKT activation and to induce cancer cell apoptosis. Together, our data illustrate a new RXRα ligand with a unique RXRα binding mode and the abilities to regulate TR3 activity indirectly and to induce TNFα-mediated cancer cell apoptosis by targeting RXRα/tRXRα.
Keywords NSC-640358      ligand      RXRα      tRXRα      TNFα      apoptosis     
Corresponding Author(s): Xiao-kun Zhang,Hu Zhou   
Issue Date: 11 September 2015
 Cite this article:   
Fan Chen,Jiebo Chen,Jiacheng Lin, et al. NSC-640358 acts as RXRα ligand to promote TNFα-mediated apoptosis of cancer cell[J]. Protein Cell, 2015, 6(9): 654-666.
 URL:  
https://academic.hep.com.cn/pac/EN/10.1007/s13238-015-0178-9
https://academic.hep.com.cn/pac/EN/Y2015/V6/I9/654
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