RESUMO
A truncated version of retinoid X receptor-α, tRXR-α, promotes cancer cell survival by activating the phosphoinositide 3-kinase (PI3K)/AKT pathway. However, targeting the tRXR-α-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-α-mediated PI3K/AKT pathway. CF31 binds RXR-α and its binding results in inhibition of RXR-α transactivation. Through RXR-α mutational analysis and computational studies, we show that Arg316 of RXR-α, known to form salt bridges with certain RXR-α 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-α. CF31 is a potent inhibitor of AKT activation in various cancer cell lines. When combined with TNF-α, it suppresses TNF-α activation of AKT by inhibiting TNF-α-induced tRXR-α interaction with the p85α regulatory subunit of PI3K. CF31 inhibition of TNF-α activation of AKT also results in TNF-α-dependent activation of caspase-8 and apoptosis. Together, our results show that CF31 is an effective converter of TNF-α signaling from survival to death by targeting tRXR-α 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.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Fitoterapia/métodos , Receptor X Retinoide alfa/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Apoptose/fisiologia , Western Blotting , Clusiaceae/química , Humanos , Imunoprecipitação , Microscopia de Fluorescência , Modelos Moleculares , Caules de Planta/química , Xantonas/química , Xantonas/farmacologiaRESUMO
Two new xanthone glycosides, namely pruniflorosides A and B (1, 2), a new benzophenone glycoside, prunifloroside C (3), and a new xanthone, pruniflorone S (4) were isolated from the stems of Cratoxylum formosum ssp. pruniflorum, along with six known xanthones (5-10). Their structures were determined on the basis of extensive spectroscopic analysis. In addition, their retinoid X receptor α (RXRα) transcriptional activities were evaluated in vitro.
Assuntos
Benzofenonas/química , Clusiaceae/química , Glicosídeos/química , Caules de Planta/química , Xantonas/química , Benzofenonas/isolamento & purificação , Benzofenonas/metabolismo , Linhagem Celular , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Medicamentos de Ervas Chinesas/metabolismo , Glicosídeos/isolamento & purificação , Glicosídeos/metabolismo , Humanos , Receptor X Retinoide alfa/metabolismo , Xantonas/isolamento & purificação , Xantonas/metabolismoRESUMO
Six new compounds, pruniflorones M-R (1-6), together with 19 known compounds (7-25) were isolated from the stems of Cratoxylum formosum ssp. pruniflorum. The structures of the new compounds were established on the basis of extensive spectroscopic data interpretation. In addition, their RXRalpha transcriptional activities were evaluated using an in vitro assay.