Document Detail


Targeting truncated retinoid X receptor-α by CF31 induces TNF-α-dependent apoptosis.
MedLine Citation:
PMID:  23151904     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Guang-Hui Wang; Fu-Quan Jiang; Ying-Hui Duan; Zhi-Ping Zeng; Fan Chen; Yi Dai; Jie-Bo Chen; Jin-Xing Liu; Jie Liu; Hu Zhou; Hai-Feng Chen; Jin-Zhang Zeng; Ying Su; Xin-Sheng Yao; Xiao-Kun Zhang
Related Documents :
23691924 - Carbon monoxide exposure improves immune function in lupus-prone mice.
24830384 - Stimulation of mesenchymal stromal cells (mscs) via tlr3 reveals a novel mechanism of a...
24697204 - Role of ksrp in control of type i interferon and cytokine expression.
24080534 - Fodipir and its dephosphorylated derivative dipyridoxyl ethyldiamine are involved in ma...
20663294 - Hyperglycemia, oxidative and nitrosative stress affect antiviral, inflammatory and apop...
21924374 - Autophagy: cellular defense to excessive inflammation.
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-11-14
Journal Detail:
Title:  Cancer research     Volume:  73     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-04     Completed Date:  2013-02-27     Revised Date:  2014-04-16    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  307-18     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*,  physiology
Blotting, Western
Clusiaceae / chemistry
Humans
Immunoprecipitation
Microscopy, Fluorescence
Models, Molecular
Phytotherapy / methods*
Plant Stems / chemistry
Retinoid X Receptor alpha / antagonists & inhibitors*
Signal Transduction / drug effects*
Tumor Necrosis Factor-alpha / metabolism*
Xanthones / chemistry,  pharmacology
Grant Support
ID/Acronym/Agency:
CA140980/CA/NCI NIH HHS; GM089927/GM/NIGMS NIH HHS; P30 CA030199/CA/NCI NIH HHS; R01 CA140980/CA/NCI NIH HHS; R01 GM089927/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/CF31 xanthone; 0/Retinoid X Receptor alpha; 0/Tumor Necrosis Factor-alpha; 0/Xanthones
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  A preclinical mouse model of invasive lobular breast cancer metastasis.
Next Document:  National trends in incidence rates of hospitalization for stroke in children with sickle cell diseas...