NSC-640358 acts as RXRa ligand to promote TNFa-mediated apoptosis of cancer cell

Retinoid X receptor a (RXRα) and its N-terminally trun- cated version tRXRα play important roles in tumorige. nesis, while some RXRg ligands possess potent anti- cancer activities by targeting and modulating the tumorigenic effects of RXRo and tRXRa. Here we describe NSC-640358 (N-6), a thiazolyl-py...

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Veröffentlicht in:蛋白质与细胞:英文版 2015 (9), p.654-666
1. Verfasser: Fan Chen Jiebo Chen Jiacheng Lin Anton V. Cheltsov Lin Xu Ya Chen Zhiping Zeng Liqun Chen Mingfeng Huang Mengjie Hu Xiaohong Ye YuqiZhou Guanghui Wang Ying su Long Zhang Fangfang Zhou Xiao-kun Zhang HU Zhou
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Zusammenfassung:Retinoid X receptor a (RXRα) and its N-terminally trun- cated version tRXRα play important roles in tumorige. nesis, while some RXRg ligands possess potent anti- cancer activities by targeting and modulating the tumorigenic effects of RXRo and tRXRa. 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 RXRa and inhibits the transactivation of RXRα homod- imer and RXRa/TR3 heterodimer. Using mutational analysis and computational study, we determine that Arg316 in RXRa, essential for 9-cis-retinoic acid binding and activating RXRg 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 w-w 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 RXRa-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 a (TNFα)-induced AKT activation and stimulates TNFa-mediated apoptosis in cancer cells in an RXRa/tRXRo dependent manner.The inhibition of TNFα-induced tRXRα/p85α complex formation by N-6 implies that N-6 targets tRXRa to inhibit TNFα-induced AKT activation and to induce cancer cell apoptosis. Together, our data illustrate a new RXRa ligand with a unique RXRα binding mode and the abilities to regulate TR3 activity indirectly and to induce TNFa-mediated cancer cell apoptosis by targeting RXRα/tRXRα.
ISSN:1674-800X
1674-8018