Heat Shock Protein 90α Recruits FLIPS to the Death-Inducing Signaling Complex and Contributes to TRAIL Resistance in Human Glioma

Abstract

Heat shock protein 90 (HSP90) is a molecular chaperone that contributes to the proper folding and stability of target proteins. Because HSP90 has been suggested to interact with FLIP_S, the key regulator of tumor necrosis factor-α–related apoptosis-inducing ligand (TRAIL)–induced apoptosis in glioma cells, we examined the role HSP90 played in controlling TRAIL response. HSP90α was found to associate with FLIP_S in resting cells in a manner dependent on the ATP-binding NH₂-terminal domain of HSP90α. Following TRAIL exposure, HSP90α and the client FLIP_S protein were recruited to the death-inducing signaling complex (DISC). Short interfering RNA–mediated suppression of HSP90α did not alter the total cellular levels of FLIP_S, but rather inhibited the recruitment of FLIP_S and other antiapoptotic proteins such as RIP and FLIP_L to the DISC, and sensitized otherwise resistant glioma cells to TRAIL-induced apoptosis. These results show that HSP90α, by localizing FLIP_S to the DISC, plays a key role in the resistance of tumor cells to TRAIL, and perhaps other proapoptotic agents. The results also define a novel means of apoptotic control by a HSP90α that may in turn help explain the global antiapoptotic effects of this protein. [Cancer Res 2007;67(19):9482–9]