title: NSC-640358 acts as RXRα ligand to promote TNFα-mediated apoptosis of cancer cell.
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.
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102 China.|School of Biological Science and Biotechnology, Minnan Normal University, Zhangzhou, 363000 China.
authors.forename: Fan
authors.initials: F
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102 China.
authors.forename: Jiebo
authors.initials: J
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102 China.
authors.forename: Jiacheng
authors.initials: J
authors.lastname: Lin
authors.affiliation: Q-MOL LLC, San Diego, CA 92105 USA.
authors.forename: Anton V
authors.initials: AV
authors.lastname: Cheltsov
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102 China.
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.affiliation: Cancer Center, Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037 USA.
authors.forename: Ya
authors.initials: Y
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102 China.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102 China.
authors.forename: Liqun
authors.initials: L
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102 China.
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102 China.
authors.forename: Mengjie
authors.initials: M
authors.lastname: Hu
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102 China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Ye
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102 China.
authors.forename: Yuqi
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102 China.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102 China.|Cancer Center, Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037 USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
authors.affiliation: Life Science Institute, Zhejiang University, Hangzhou, 310058 China.
authors.forename: Long
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, 215123 China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Zhou
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102 China.|Cancer Center, Sanford-Burnham Medical Research Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037 USA.
authors.forename: Xiao-Kun
authors.initials: XK
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361102 China.
authors.forename: Hu
authors.initials: H
authors.lastname: Zhou
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism; D010091:Oximes / Q000378:metabolism* / Q000494:pharmacology*; D011487:Protein Conformation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011720:Pyrazoles / Q000378:metabolism* / Q000494:pharmacology*; D047490:Retinoid X Receptor alpha / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013844:Thiazoles / Q000378:metabolism* / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D008024:Ligands; C000607790:NSC-640358; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010091:Oximes; D011720:Pyrazoles; D047490:Retinoid X Receptor alpha; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt