The Small Heat Shock Protein B-crystallin Is a Novel Inhibitor of TRAIL-induced Apoptosis That Suppresses the Activation of Caspase-3
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor α family of cytokines that preferentially induces apoptosis in transformed cells, making it a promising cancer therapy. However, many neoplasms are resistant to TRAIL-induced apoptosis by mechanisms that are poorly understood. We demonstrate that the expression of the small heat shock protein αB-crystallin (but not other heat shock proteins or apoptosis-regulating proteins) correlates with TRAIL resistance in a panel of human cancer cell lines. Stable expression of wild-type αB-crystallin, but not a pseudophosphorylation mutant impaired in its assembly and chaperone function, protects cancer cells from TRAIL-induced caspase-3 activation and apoptosis in vitro. Furthermore, selective inhibition of αB-crystallin expression by RNA interference sensitizes cancer cells to TRAIL. In addition, wild-type αB-crystallin promotes xenograft tumor growth and inhibits TRAIL-induced apoptosis in vivo in nude mice, whereas a pseudophosphorylation αB-crystallin mutant impaired in its anti-apoptotic function inhibits xenograft tumor growth. Collectively, these findings indicate that αB-crystallin is a novel regulator of TRAIL-induced apoptosis and tumor growth. Moreover, these results demonstrate that targeted inhibition of αB-crystallin promotes TRAIL-induced apoptosis, thereby suggesting a novel strategy to overcome TRAIL resistance in cancer.
Kamradt M.C., Lu M., Werner M.E., Kwan T., Chen F., Strohecker A., ...Cryns V.L. (2005). The small heat shock protein B-crystallin is a novel inhibitor of TRAIL-induced apoptosis that suppresses the activation of caspase-3. Journal of Biological Chemistry, 280(12), 11059-11066.
Virtual Commons Citation
Krevosky, Merideth; Lu, M.; Werner, M. E.; Kwan, T.; Chen, F.; Strohecker, A.; Oshita, S.; Wilkinson, J. C.; Yu, C.; Oliver, P. G.; Duckett, C. S.; Buchsbaum, D. J.; LoBuglio, A. F.; Jordan, V. C.; and Cryns, V. L. (2005). The Small Heat Shock Protein B-crystallin Is a Novel Inhibitor of TRAIL-induced Apoptosis That Suppresses the Activation of Caspase-3. In Biological Sciences Faculty Publications. Paper 13.
Available at: http://vc.bridgew.edu/biol_fac/13