Breast Cancer Research and Treatment

, Volume 124, Issue 2, pp 307–315

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
Preclinical study

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.

Keywords

Heat shock protein HspB2 MKBP Apoptosis TRAIL TNF-α 

Copyright information

© Springer Science+Business Media, LLC. 2010

Authors and Affiliations

  • Shayna E. Oshita
    • 1
  • Feng Chen
    • 1
  • Toni Kwan
    • 1
  • Fruma Yehiely
    • 1
  • Vincent L. Cryns
    • 1
  1. 1.Cell Death Regulation Laboratory, Departments of Medicine and Cell and Molecular Biology, Robert H. Lurie Comprehensive Cancer Center, Lurie 4-113, Feinberg School of MedicineNorthwestern UniversityChicagoUSA

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