title: Targeting truncated retinoid X receptor-α by CF31 induces TNF-α-dependent apoptosis.
abstract: 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.
authors.affiliation: School of Pharmaceutical Science, Xiamen University, Xiamen, China.
authors.forename: Guang-Hui
authors.initials: GH
authors.lastname: Wang
authors.forename: Fu-Quan
authors.initials: FQ
authors.lastname: Jiang
authors.forename: Ying-Hui
authors.initials: YH
authors.lastname: Duan
authors.forename: Zhi-Ping
authors.initials: ZP
authors.lastname: Zeng
authors.forename: Fan
authors.initials: F
authors.lastname: Chen
authors.forename: Yi
authors.initials: Y
authors.lastname: Dai
authors.forename: Jie-Bo
authors.initials: JB
authors.lastname: Chen
authors.forename: Jin-Xing
authors.initials: JX
authors.lastname: Liu
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Hu
authors.initials: H
authors.lastname: Zhou
authors.forename: Hai-Feng
authors.initials: HF
authors.lastname: Chen
authors.forename: Jin-Zhang
authors.initials: JZ
authors.lastname: Zeng
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
authors.forename: Xin-Sheng
authors.initials: XS
authors.lastname: Yao
authors.forename: Xiao-Kun
authors.initials: XK
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D015153:Blotting, Western; D028084:Clusiaceae / Q000737:chemistry; D006801:Humans; D047468:Immunoprecipitation; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D008517:Phytotherapy / Q000379:methods*; D018547:Plant Stems / Q000737:chemistry; D047490:Retinoid X Receptor alpha / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D044004:Xanthones / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C578498:CF31 xanthone; D047490:Retinoid X Receptor alpha; D014409:Tumor Necrosis Factor-alpha; D044004:Xanthones