NSC-640358 acts as RXRα ligand to promote TNFα-mediated apoptosis of cancer cell.

Fan Chen; Jiebo Chen; Jiacheng Lin; Anton V Cheltsov; Lin XU; Ya Chen; Zhiping Zeng; Liqun Chen; Mingfeng Huang; Mengjie HU; Xiaohong YE; Yuqi Zhou; Guanghui Wang; Ying SU; Long Zhang; Fangfang Zhou; Xiao-kun Zhang; Hu Zhou

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NSC-640358 acts as RXRα ligand to promote TNFα-mediated apoptosis of cancer cell.

Author: Fan CHEN ¹ ; Jiebo CHEN ¹ ; Jiacheng LIN ¹ ; Anton V CHELTSOV ² ; Lin XU ¹ ; Ya CHEN ³ ; Zhiping ZENG ¹ ; Liqun CHEN ¹ ; Mingfeng HUANG ¹ ; Mengjie HU ¹ ; Xiaohong YE ¹ ; Yuqi ZHOU ¹ ; Guanghui WANG ¹ ; Ying SU ¹ ; Long ZHANG ⁴ ; Fangfang ZHOU ⁵ ; Xiao-Kun ZHANG ¹ ; Hu ZHOU ¹
Author Information

1. School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102 China.
2. Q-MOL LLC, San Diego, CA 92105 USA.
3. Cancer Center, Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037 USA.
4. Life Science Institute, Zhejiang University, Hangzhou, 310058 China.
5. Institutes of Biology and Medical Sciences, Soochow University, Suzhou, 215123 China.
Publication Type:Journal Article
MeSH: Apoptosis; drug effects; Cell Line, Tumor; Enzyme Activation; drug effects; Humans; Ligands; Molecular Docking Simulation; Nuclear Receptor Subfamily 4, Group A, Member 1; genetics; metabolism; Oximes; metabolism; pharmacology; Protein Conformation; Proto-Oncogene Proteins c-akt; metabolism; Pyrazoles; metabolism; pharmacology; Retinoid X Receptor alpha; chemistry; genetics; metabolism; Thiazoles; metabolism; pharmacology; Transcription, Genetic; drug effects; Transcriptional Activation; drug effects; Tumor Necrosis Factor-alpha; metabolism
From: Protein & Cell 2015;6(9):654-666
CountryChina
Language:English
Abstract: Retinoid X receptor α (RXRα) and its N-terminally truncated version tRXRα play important roles in tumorigenesis, while some RXRα ligands possess potent anti-cancer 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.