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J. Biol. Chem., Vol. 280, Issue 12, 11059-11066, March 25, 2005
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The Small Heat Shock Protein 
B-crystallin Is a Novel Inhibitor of TRAIL-induced Apoptosis That Suppresses the Activation of Caspase-3*
¶¶¶
From the
Cell Death Regulation Laboratory, Departments of Medicine and Cell and Molecular Biology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, ||Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, **Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, Chicago, Illinois 60637, and Departments of Radiation Oncology and Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor 
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 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 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 B-crystallin expression by RNA interference sensitizes cancer cells to TRAIL. In addition, wild-type B-crystallin promotes xenograft tumor growth and inhibits TRAIL-induced apoptosis in vivo in nude mice, whereas a pseudophosphorylation B-crystallin mutant impaired in its anti-apoptotic function inhibits xenograft tumor growth. Collectively, these findings indicate that B-crystallin is a novel regulator of TRAIL-induced apoptosis and tumor growth. Moreover, these results demonstrate that targeted inhibition of B-crystallin promotes TRAIL-induced apoptosis, thereby suggesting a novel strategy to overcome TRAIL resistance in cancer.
Received for publication, November 29, 2004 , and in revised form, January 14, 2005.
* This work was supported by Grant R01CA097198 (to V. L. C.), Specialized Programs of Research Excellence in Breast Cancer Grant P50CA89018 (to V. C. J. and V. L. C.), Grant T32CA70085 (to M. C. K.), Grant T32DK07169 (to M. E. W. and S. O.), and Specialized Programs of Research Excellence in Breast Cancer Grant P50CA89019 (to D. J. B. and A. F. L.) from the National Institutes of Health; by Grants DAMD17-02-1-0526 (to V. L. C.), DAMD17-03-1-0426 (to V. L. C.), DAMD17-00-1-0386 (to A. S.), and DAMD17-02-1-0264 (to D. J. B.) from the Department of Defense Breast Cancer Research Program; and by the Avon Foundation Breast Cancer Research and Care Program (to V. L. C., V. C. J., A. F. L., and D. J. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
¶ Present address: Dept. of Biology, Bridgewater State College, Bridgewater, MA 02325.
¶¶ To whom correspondence should be addressed: Tarry 15-755, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Ave., Chicago, IL 60611. Tel.: 312-503-0644; Fax: 312-908-9032; E-mail: v-cryns{at}northwestern.edu.
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