title: 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.affiliation: Cell Death Regulation Laboratory, Department of Medicine and Cell, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.
authors.forename: Merideth C
authors.initials: MC
authors.lastname: Kamradt
authors.forename: Meiling
authors.initials: M
authors.lastname: Lu
authors.forename: Michael E
authors.initials: ME
authors.lastname: Werner
authors.forename: Toni
authors.initials: T
authors.lastname: Kwan
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.forename: Anne
authors.initials: A
authors.lastname: Strohecker
authors.forename: Shayna
authors.initials: S
authors.lastname: Oshita
authors.forename: John C
authors.initials: JC
authors.lastname: Wilkinson
authors.forename: Chunjiang
authors.initials: C
authors.lastname: Yu
authors.forename: Patsy G
authors.initials: PG
authors.lastname: Oliver
authors.forename: Colin S
authors.initials: CS
authors.lastname: Duckett
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Buchsbaum
authors.forename: Albert F
authors.initials: AF
authors.lastname: LoBuglio
authors.forename: V Craig
authors.initials: VC
authors.lastname: Jordan
authors.forename: Vincent L
authors.initials: VL
authors.lastname: Cryns
mesh_terms: 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*
chemical_list: 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