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

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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.

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Acknowledgments

We are indebted to Drs. Honglin Li (Northwestern University) and Marcus Peter (University of Chicago) for providing reagents. These studies were supported by Department of Defense CDMRP grant DAMD17-03-1-0426 (VLC), NIH grants R01CA097198 (VLC) and T32DK007169 (SO), and by the Breast Cancer Research Foundation (VLC).

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  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 Medicine, Northwestern University, 303 East Superior Street, Chicago, IL, 60611, USA

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

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  1. Shayna E. Oshita
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  2. Feng Chen
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Correspondence to Vincent L. Cryns.

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Oshita, S.E., Chen, F., Kwan, T. et al. The small heat shock protein HspB2 is a novel anti-apoptotic protein that inhibits apical caspase activation in the extrinsic apoptotic pathway. Breast Cancer Res Treat 124, 307–315 (2010). https://doi.org/10.1007/s10549-010-0735-0

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  • DOI: https://doi.org/10.1007/s10549-010-0735-0

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