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Targeting Prostate Cancer Stemlike Cells Through Cell Surface-Expressed GRP78

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Technical Report,30 Sep 2014,29 Sep 2015

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Duke University Durham United States

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This proposal investigates cell surface GRP78 as a target for eliminating prostate cancer stem-like cells. In period 2,we demonstrated that prostate cancer cells are heterogeneous, being composed of cell surface GRP78 and cellsurface GRP78- tumor cells. In the current period period 3, we implement cell sorting to isolate cell surface GRP78 and cell surface GRP78- prostate cancer cell populations. We demonstrate that the cell surface GRP78 tumor cells, but not the cell surface GRP78- cells, exhibit self renewing activity in a sphere forming assay an activity associated with cancer stemness. We also show that the cell surface GRP78-expressing subpopulation of cells supports nuclear AktGSK-3Snail-1 signaling. These findings are important because they are the first to suggest that GRP78 regulates the activity of nuclear Akt, which has been implicated in therapy resistance Bozulic, L, Surucu,B, Hynx, D, and Hemmings, BA. 2008. PKBalphaAkt1 acts downstream of DNA-PK in the DNA double-strand break response and promotes survival. Mol. Cell. 30203-13. Due to a loss of critical personnel in the laboratory of Dr. Chi co-investigator, we were unable to test the hypothesis that cell surface GRP78 prostate cancer cells exhibit increased tumor initiating activity compared to negative cells using a xenograft model. We obtained a one year, no-cost extension for the remaining budget of the grant, which will allow us to perform these important animal studies, thus completing the original tasks outlined in the approved statement of work.


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