NSC-640358 acts as RXR? ligand to promote TNF?-mediated apoptosis of cancer cell.

ABSTRACT: Retinoid X receptor ? (RXR?) and its N-terminally truncated version tRXR? play important roles in tumorigenesis, while some RXR? ligands possess potent anti-cancer activities by targeting and modulating the tumorigenic effects of RXR? and tRXR?. Here we describe NSC-640358 (N-6), a thiazolyl-pyrazole derived compound, acts as a selective RXR? ligand to promote TNF?-mediated apoptosis of cancer cell. N-6 binds to RXR? and inhibits the transactivation of RXR? homodimer and RXR?/TR3 heterodimer. Using mutational analysis and computational study, we determine that Arg316 in RXR?, essential for 9-cis-retinoic acid binding and activating RXR? transactivation, is not required for antagonist effects of N-6, whereas Trp305 and Phe313 are crucial for N-6 binding to RXR? by forming extra ?-? stacking interactions with N-6, indicating a distinct RXR? binding mode of N-6. N-6 inhibits TR3-stimulated transactivation of Gal4-DBD-RXR?-LBD by binding to the ligand binding pocket of RXR?-LBD, suggesting a strategy to regulate TR3 activity indirectly by using small molecules to target its interacting partner RXR?. For its physiological activities, we show that N-6 strongly inhibits tumor necrosis factor ? (TNF?)-induced AKT activation and stimulates TNF?-mediated apoptosis in cancer cells in an RXR?/tRXR? dependent manner. The inhibition of TNF?-induced tRXR?/p85? complex formation by N-6 implies that N-6 targets tRXR? to inhibit TNF?-induced AKT activation and to induce cancer cell apoptosis. Together, our data illustrate a new RXR? ligand with a unique RXR? binding mode and the abilities to regulate TR3 activity indirectly and to induce TNF?-mediated cancer cell apoptosis by targeting RXR?/tRXR?.

SUBMITTER: Chen F 

PROVIDER: S-EPMC4537469 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature