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Background  Cellular FLICE-Inhibitory Protein (long form, c-FLIP L ) is a critical negative regulator of death receptor-mediated apoptosis. Overexpression of c-FLIP L  has been reported in many cancer cell lines and is associated with chemoresistance. In contrast, down-regulation of c-FLIP may drive cancer cells into cellular apoptosis. This study aims to demonstrate that inhibition of the heat shock protein 90 (Hsp90) either by inhibitors geldanamycin/17-N-Allylamino-17-demethoxygeldanamycin (GA/17-AAG) or siRNA technique in human lung cancer cells induces c-FLIP L  degradation and cellular apoptosis through C-terminus of Hsp70-interacting protein (CHIP)-mediated mechanisms.    Methods  Calu-1 and H157 cell lines (including H157-c-FLIP L  overexpressing c-FLIP L  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 α/β proteins were knocked down by siRNA technique. CHIP and c-FLIP L  plasmids were transfected into cells and immunoprecipitation experiments were performed to testify the interactions between c-FLIP L , CHIP and Hsp90.    Results  c-FLIP L  down-regulation induced by 17-AAG can be reversed with the proteasome inhibitor MG132, which suggested that c-FLIP L  degradation is mediated by a ubiquitin-proteasome system. Inhibition of Hsp90α/β reduced c-FLIP L  level, whereas knocking down CHIP expression with siRNA technique inhibited c-FLIP L  degradation. Furthermore, c-FLIP L  and CHIP were co-precipitated in the IP complexes. In addition, overexpression of c-FLIP L  can rescue cancer cells from apoptosis. When 17-AAG was combined with an anti-cancer agent celecoxib(CCB), c-FLIP L  level declined further and there was a higher degree of caspase activation.    Conclusion  We have elucidated c-FLIP L  degradation contributes to apoptosis induced by Hsp90 inhibition, suggesting c-FLIP and Hsp90 may be the promising combined targets in human lung cancer treatment.

Down-regulation of cellular FLICE-inhibitory protein (Long Form) contributes to apoptosis induced by Hsp90 inhibition in human lung cancer cells