Targeting Prostate Cancer Stemlike Cells Through Cell Surface-Expressed GRP78
Abstract
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 Akt/GSK-3/Snail-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. PKBalpha/Akt1 acts downstream of DNA-PK in the DNA double-strand break response and promotes survival. Mol. Cell. 30:203-13). 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2015
- Accession Number
- AD1004919
Entities
People
- Robin E. Bachelder
- Salvatore Pizzo
Organizations
- Duke University