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- W2016285199 abstract "Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, ILExpression of clusterin (CLU) closely correlates with regulation of apoptosis in cancer. While endoplasmic reticulum (ER) stress-induced up-regulation and retro-translocation of cytoplasmic CLU (cCLU)(also termed as presecretory and secreted forms, psCLU and sCLU) has been linked to its anti-apoptotic properties, the mechanism mediating these processes remain undefined. Here, we show that GRP78 (Bip) associates with cCLU to facilitate its retro-translocation and redistribution to the mitochondria in human prostate cancer cells. We found that ER stress inducers, such as TG or MG132, increased expression levels of both cCLU and GRP78 proteins and led to the association of these two proteins. Furthermore, GRP78 overexpression resulted in increased cCLU but reduced sCLU levels secreted into the culture media. GRP78 stabilized cCLU protein and its hypo-glycosylated forms, in particular after paclitaxel treatment. Moreover, subcellular fractionation studies indicated GRP78 increased stress-induced cCLU retro-translocation from the ER with redistribution to the mitochondria. Live cell imaging revealed that a CLUGFP localized directly to highly mobile mitochondria. Co-expression of both GRP78 and CLU in LNCaP cells led to increased CLUGFP -mitochondria co-localization and reduced apoptosis by cooperatively stabilizing mitochondrial membrane integrity. Transient depletion of GRP78 reduced cCLU protein but not mRNA transcript levels, accompanied by cell cycle arrest at G0/G1 with down-regulation of both phospho-Rb and cyclin D1, and synergistic increases in paclitaxel-induced cell apoptosis. Taken together, our findings reveal a novel role of GRP78 in the regulation of CLU retro-translocation and its redistribution to the mitochondria, suggesting that GRP78 and CLU cooperatively promote survival during ER stress in prostate cancer.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3261. doi:1538-7445.AM2012-3261" @default.
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- W2016285199 date "2012-04-15" @default.
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- W2016285199 title "Abstract 3261: GRP78 regulates clusterin stability, retrotranslocation, and mitochondrial localization under ER stress in prostate cancer" @default.
- W2016285199 doi "https://doi.org/10.1158/1538-7445.am2012-3261" @default.
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