Heat shock protein 90alpha recruits FLIPS to the death-inducing signaling complex and contributes to TRAIL resistance in human glioma.
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-alpha-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in glioma cells, we examined the role HSP90 played in controlling TRAIL response. HSP90alpha was found to associate with FLIP(S) in resting cells in a manner dependent on the ATP-binding NH2-terminal domain of HSP90alpha. Following TRAIL exposure, HSP90alpha and the client FLIP(S) protein were recruited to the death-inducing signaling complex (DISC). Short interfering RNA-mediated suppression of HSP90alpha 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 HSP90alpha, 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 HSP90alpha that may in turn help explain the global antiapoptotic effects of this protein.
Panner
Amith
A
Department of Neurological Surgery, University of California-San Francisco, San Francisco, California 94115-0875, USA.
Murray
Joseph C
JC
Berger
Mitchel S
MS
Pieper
Russell O
RO
D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053418:Death Domain Receptor Signaling Adaptor Proteins; D018841:HSP90 Heat-Shock Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D000255:Adenosine Triphosphate