The small heat shock protein alpha 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 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.
Kamradt
Merideth C
MC
Cell Death Regulation Laboratory, Department of Medicine and Cell, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.
Lu
Meiling
M
Werner
Michael E
ME
Kwan
Toni
T
Chen
Feng
F
Strohecker
Anne
A
Oshita
Shayna
S
Wilkinson
John C
JC
Yu
Chunjiang
C
Oliver
Patsy G
PG
Duckett
Colin S
CS
Buchsbaum
Donald J
DJ
LoBuglio
Albert F
AF
Jordan
V Craig
VC
Cryns
Vincent L
VL
D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D001943:Breast Neoplasms / Q000473:pathology; D053148:Caspase 3; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D034622:RNA Interference; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D038203:alpha-Crystallin B Chain / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D061945:Caspase Inhibitors; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D038203:alpha-Crystallin B Chain; C505407:CASP3 protein, human; D053148:Caspase 3