Targeting truncated retinoid X receptor-? by CF31 induces TNF-?-dependent apoptosis.

ABSTRACT: A truncated version of retinoid X receptor-?, tRXR-?, promotes cancer cell survival by activating the phosphoinositide 3-kinase (PI3K)/AKT pathway. However, targeting the tRXR-?-mediated survival pathway for cancer treatment remains to be explored. We report here our identification of a new natural product molecule, CF31, a xanthone isolated from Cratoxylum formosum ssp. pruniflorum, and the biologic evaluation of its regulation of the tRXR-?-mediated PI3K/AKT pathway. CF31 binds RXR-? and its binding results in inhibition of RXR-? transactivation. Through RXR-? mutational analysis and computational studies, we show that Arg316 of RXR-?, known to form salt bridges with certain RXR-? ligands, such as 9-cis-retinoic acid (9-cis-RA), is not required for the antagonist effect of CF31, showing a distinct binding mode. Evaluation of several CF31 analogs suggests that the antagonist effect is mainly attributed to an interference with Leu451 of helix H12 in RXR-?. CF31 is a potent inhibitor of AKT activation in various cancer cell lines. When combined with TNF-?, it suppresses TNF-? activation of AKT by inhibiting TNF-?-induced tRXR-? interaction with the p85? regulatory subunit of PI3K. CF31 inhibition of TNF-? activation of AKT also results in TNF-?-dependent activation of caspase-8 and apoptosis. Together, our results show that CF31 is an effective converter of TNF-? signaling from survival to death by targeting tRXR-? in a unique mode and suggest that identification of a natural product that targets an RXR-mediated cell survival pathway that regulates PI3K/AKT may offer a new therapeutic strategy to kill cancer cells.

SUBMITTER: Wang GH 

PROVIDER: S-EPMC3537848 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature