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Open Access Highly Accessed Research article

Bcl-2 associated athanogene 5 (Bag5) is overexpressed in prostate cancer and inhibits ER-stress induced apoptosis

Anja Bruchmann1, Corinna Roller1, Tamara Vanessa Walther1, Georg Schäfer2, Sara Lehmusvaara3, Tapio Visakorpi3, Helmut Klocker2, Andrew C B Cato1 and Danilo Maddalo1*

Author Affiliations

1 Karlsruhe Institute of Technology, Institute of Toxicology and Genetics, Hermann-von-Helmholtz Platz 1, Eggenstein-Leopoldshafen 76344, Germany

2 Division of Experimental Urology, Department of Urology, Innsbruck Medical University, Innsbruck, Austria

3 Institute of Biomedical Technology and BioMediTech, University of Tampere and Tampere University Hospital, Tampere FI-33014, Finland

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BMC Cancer 2013, 13:96  doi:10.1186/1471-2407-13-96

Published: 1 March 2013

Abstract

Background

The Bag (Bcl-2 associated athanogene) family of proteins consists of 6 members sharing a common, single-copied Bag domain through which they interact with the molecular chaperone Hsp70. Bag5 represents an exception in the Bag family since it consists of 5 Bag domains covering the whole protein. Bag proteins like Bag1 and Bag3 have been implicated in tumor growth and survival but it is not known whether Bag5 also exhibits this function.

Methods

Bag5 mRNA and protein expression levels were investigated in prostate cancer patient samples using real-time PCR and immunoblot analyses. In addition immunohistological studies were carried out to determine the expression of Bag5 in tissue arrays. Analysis of Bag5 gene expression was carried out using one-way ANOVA and Bonferroni’s Multiple Comparison test. The mean values of the Bag5 stained cells in the tissue array was analyzed by Mann-Whitney test. Functional studies of the role of Bag5 in prostate cancer cell lines was performed using overexpression and RNA interference analyses.

Results

Our results show that Bag5 is overexpressed in malignant prostate tissue compared to benign samples. In addition we could show that Bag5 levels are increased following endoplasmic reticulum (ER)-stress induction, and Bag5 relocates from the cytoplasm to the ER during this process. We also demonstrate that Bag5 interacts with the ER-resident chaperone GRP78/BiP and enhances its ATPase activity. Bag5 overexpression in 22Rv.1 prostate cancer cells inhibited ER-stress induced apoptosis in the unfolded protein response by suppressing PERK-eIF2-ATF4 activity while enhancing the IRE1-Xbp1 axis of this pathway. Cells expressing high levels of Bag5 showed reduced sensitivity to apoptosis induced by different agents while Bag5 downregulation resulted in increased stress-induced cell death.

Conclusions

We have therefore shown that Bag5 is overexpressed in prostate cancer and plays a role in ER-stress induced apoptosis. Furthermore we have identified GRP78/BiP as a novel interaction partner of Bag5.

Keywords:
Unfolded protein response; Cell stress; Endoplasmic reticulum; Apoptosis; Molecular chaperones; Refolding