The small heat shock protein alpha B-crystallin is a novel inhibitor of TRAIL-induced apoptosis that suppresses the activation of caspase-3.

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor alpha 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 alpha B-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 alpha B-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 alpha B-crystallin expression by RNA interference sensitizes cancer cells to TRAIL. In addition, wild-type alpha B-crystallin promotes xenograft tumor growth and inhibits TRAIL-induced apoptosis in vivo in nude mice, whereas a pseudophosphorylation alpha B-crystallin mutant impaired in its anti-apoptotic function inhibits xenograft tumor growth. Collectively, these findings indicate that alpha B-crystallin is a novel regulator of TRAIL-induced apoptosis and tumor growth. Moreover, these results demonstrate that targeted inhibition of alpha B-crystallin promotes TRAIL-induced apoptosis, thereby suggesting a novel strategy to overcome TRAIL resistance in cancer.

• Authors: Merideth C Kamradt, Meiling Lu, Michael E Werner, Toni Kwan, Feng Chen, Anne Strohecker, Shayna Oshita, John C Wilkinson, Chunjiang Yu, Patsy G Oliver, Colin S Duckett, Donald J Buchsbaum, Albert F LoBuglio, V Craig Jordan, Vincent L Cryns
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 280 Issue 12 Pg. 11059-66 (Mar 25 2005) ISSN: 0021-9258 [Print] United States
• PMID: 15653686 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Apoptosis Regulatory Proteins
• Caspase Inhibitors
• Membrane Glycoproteins
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• Tumor Necrosis Factor-alpha
• alpha-Crystallin B Chain
• CASP3 protein, human
• Caspase 3

Topics

• 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)
• alpha-Crystallin B Chain (physiology)