TY - JOUR
T1 - The small heat shock protein αB-crystallin is a novel inhibitor of TRAIL-induced apoptosis that suppresses the activation of caspase-3
AU - Kamradt, Merideth C.
AU - Lu, Meiling
AU - Werner, Michael E.
AU - Kwan, Toni
AU - Chen, Feng
AU - Strohecker, Anne
AU - Oshita, Shayna
AU - Wilkinson, John C.
AU - Yu, Chunjiang
AU - Oliver, Patsy G.
AU - Duckett, Colin S.
AU - Buchsbaum, Donald J.
AU - LoBuglio, Albert F.
AU - Jordan, V. Craig
AU - Cryns, Vincent L.
PY - 2005/3/25
Y1 - 2005/3/25
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M413382200
DO - 10.1074/jbc.M413382200
M3 - Article
C2 - 15653686
AN - SCOPUS:20144374696
SN - 0021-9258
VL - 280
SP - 11059
EP - 11066
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 12
ER -