The small heat shock protein HspB2 is a novel anti-apoptotic protein that inhibits apical caspase activation in the extrinsic apoptotic pathway

Shayna E. Oshita, Feng Chen, Toni Kwan, Fruma Yehiely, Vincent L. Cryns

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Members of the conserved small heat shock protein (sHSP) family, such as αB-crystallin and Hsp27, are constitutively expressed in diverse malignancies and have been linked to several hallmark features of cancer including apoptosis resistance. In contrast, the sHSP HspB2/MKBP, which shares an intergenic promoter with αB-crystallin, was discovered as a chaperone of the myotonic dystrophy protein kinase and has not been previously implicated in apoptosis regulation. Here we describe a new function for HspB2 as a novel inhibitor of apical caspase activation in the extrinsic apoptotic pathway. Specifically, we demonstrate that HspB2 is expressed in a subset of human breast cancer cell lines and that ectopic expression of HspB2 in breast cancer cells confers resistance to apoptosis induced by both TRAIL and TNF-α. We also show that HspB2 inhibits the extrinsic apoptotic pathway by suppressing apical caspases-8 and 10 activation, thereby blocking downstream apoptotic events, such as Bid cleavage and caspase-3 activation. Consistent with these in vitro effects, HspB2 attenuates the anti-tumor activity of TRAIL in an orthotopic xenograft model of breast cancer. Collectively, our results reveal a novel function of HspB2 as an anti-apoptotic protein that negatively regulates apical caspase activation in the extrinsic apoptotic pathway.

Original languageEnglish (US)
Pages (from-to)307-315
Number of pages9
JournalBreast Cancer Research and Treatment
Volume124
Issue number2
DOIs
StatePublished - Nov 2010

Keywords

  • Apoptosis
  • Heat shock protein
  • HspB2
  • MKBP
  • TNF-α
  • TRAIL

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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