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Targeting Prostate Cancer Stemlike Cells through Cell Surface Expressed GRP78

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Technical Report,30 Sep 2012,29 Sep 2016

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Duke University Durham United States

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This study investigated a function for cell surface GRP78 in regulating prostate cancer stem-like cells. In year 1, we showed that cell surface GRP78 was upregulated in prostate cancer sphere cultures compared to that in cells grown in 2D tissue culture plates, indicating enrichment of cell surface GRP78 cancer stem like cells in sphere culture. We also showed that the signaling axis activated by cell surface GRP78 is upregulated in prostate cancer cells grown in sphere culture compared those grown in adherent culture. In year 2, we showed that prostate cancer cells are heterogeneous, being composed of cell surface GRP78 and GRP78- tumor cells. By cell sorting we showed that the GRP78 prostate cancer cells, but not the GRP78- cells, exhibited cancer stem-like cell behavior. Furthermore an GRP78 monoclonal antibody inhibited sphere forming ability of GRP78 prostate cancer cells. In year 3, we demonstrated that GRP78 cells, relative to GRP78- cells, express increased phospho-Akt , increased phospho- GSK-3, and increased Snail-1. Surprisingly, the majority of phospho-Akt was localized in the nucleus of cell surface GRP78 tumor cells. Finally, we tested the hypothesis that GRP78 tumor cells exhibit increased tumor initiating activity relative to GRP78- tumor cells. These studies are still in progress, but initial results indicate that GRP78- tumor cells are more tumorigenic than GRP78 tumor cells. We postulate that the GRP78- tumor cells restored GRP78 expression in vivo in order to survive, and will test this hypothesis by harvesting tumors from animals. Collectively, our studies indicate that GRP78 drives cancer stem-like cell growth, and can be targeted with a GRP78 antibody. Future studies will investigate whether these antibodies suppress prostate cancer growth in animal models.

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  • Medicine and Medical Research

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