%0 Journal Article
%T Down-regulation of cellular FLICE-inhibitory protein (Long Form) contributes to apoptosis induced by Hsp90 inhibition in human lung cancer cells
%A Qilin Wang
%A Wendong Sun
%A Xuexi Hao
%A Tianliang Li
%A Ling Su
%A Xiangguo Liu
%J Cancer Cell International
%D 2012
%I BioMed Central
%R 10.1186/1475-2867-12-54
%X Calu-1 and H157 cell lines (including H157-c-FLIPL overexpressing c-FLIPL and control cell H157-lacZ) were treated with 17-AAG and the cell lysates were prepared to detect the given proteins by Western Blot and the cell survival was assayed by SRB assay. CHIP and Hsp90 ¦Á/¦Â proteins were knocked down by siRNA technique. CHIP and c-FLIPL plasmids were transfected into cells and immunoprecipitation experiments were performed to testify the interactions between c-FLIPL, CHIP and Hsp90.c-FLIPL down-regulation induced by 17-AAG can be reversed with the proteasome inhibitor MG132, which suggested that c-FLIPL degradation is mediated by a ubiquitin-proteasome system. Inhibition of Hsp90¦Á/¦Â reduced c-FLIPL level, whereas knocking down CHIP expression with siRNA technique inhibited c-FLIPL degradation. Furthermore, c-FLIPL and CHIP were co-precipitated in the IP complexes. In addition, overexpression of c-FLIPL can rescue cancer cells from apoptosis. When 17-AAG was combined with an anti-cancer agent celecoxib(CCB), c-FLIPL level declined further and there was a higher degree of caspase activation.We have elucidated c-FLIPL degradation contributes to apoptosis induced by Hsp90 inhibition, suggesting c-FLIP and Hsp90 may be the promising combined targets in human lung cancer treatment.Caspase-8 activation plays an important role in the death receptor-mediated extrinsic apoptotic pathway in human cancer cells [1]. When binding to ligands, the death receptor is activated and forms the death induced signal complex (DISC) together with FADD and procaspase-8. Procaspase-8 is activated and initiates the caspase cascade which mediates cellular apoptosis. c-FLIPL is a major protein that can prevent caspase-8/10 activation in the DISC and inhibiting apoptosis mediated by death receptors. It has been found that c-FLIPL is up-regulated in several carcinomas [2,3] and overexpression of c-FLIPL can be responsible for chemoresistance and malignant transformation [4-6]. To date, more than 10
%K c-FLIPL
%K Apoptosis
%K CHIP
%K Hsp90
%U http://www.cancerci.com/content/12/1/54