The Small Heat Shock Protein αB-crystallin Is a Novel Inhibitor of TRAIL-induced Apoptosis That Suppresses the Activation of Caspase-3

• Published in: The Journal of biological chemistry Vol. 280; no. 12; pp. 11059 - 11066
• Main Authors: Kamradt, Merideth C., Lu, Meiling, Werner, Michael E., Kwan, Toni, Chen, Feng, Strohecker, Anne, Oshita, Shayna, Wilkinson, John C., Yu, Chunjiang, Oliver, Patsy G., Duckett, Colin S., Buchsbaum, Donald J., LoBuglio, Albert F., Jordan, V. Craig, Cryns, Vincent L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.03.2005
• Subjects: alpha-Crystallin B Chain - physiology; Apoptosis - drug effects; Apoptosis Regulatory Proteins; Breast Neoplasms - pathology; Caspase 3; Caspase Inhibitors; Cell Line, Tumor; Enzyme Activation - drug effects; Female; Humans; Membrane Glycoproteins - antagonists & inhibitors; RNA Interference; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha - antagonists & inhibitors
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M413382200

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.