The ability of prostate cancer (PCa) cells to thrive is due to its ability to change its metabolic processes. Some of these changes include up regulation of the HDL receptor SR-B1 and the down regulation ABCA1, the protein that facilitates HDL biogenesis. New observations indicate that PCa cells and tissue store excess cholesterol in lipid droplets, which is strongly suggested to promote PCa progression and aggressiveness. Since cellular lipids drive many biological processes such as supporting membrane biogenesis and signaling, as well as being essential to androgen synthesis that promotes PCa growth, discerning how HDL uptake by SR-B1 and HDL biogenesis by ABCA1 influence PCa proliferation will aid in elucidating PCa mechanisms for progression in order to improve therapeutic interventions. Higher levels of HDL have been shown to decrease risk for many human cancers, however this correlation for PCa is still controversial. To understand the role of HDL metabolism in PCa, I will investigate the processes of HDL uptake and biogenesis by SR-B1 and ABCA1, respectively. To determine how HDL metabolism impacts PCa proliferation, SR-B1 and ABCA1 function or expression will be pharmacologically or genetically altered. Proliferation will be determined in vitro by cell counting, cell cycle will be determined by flow cytometry, lipid transport will be evaluated by lipid uptake and efflux assays, lipid accumulation will be determined by ELISA mass assays, cholesterol biochemical mass assays, and cellular staining. Signal transduction will be determined by western blot. Finally, to determine how HDL impacts PCa in vivo, a syngeneic mouse model will be used. Here PCa cells will be manipulated to have stable expression or stable knockdown of ABCA1 or SR-B1. The engineered lines will be injected into mice with genetically altered levels of HDL and observed for tumor progression. These assays will provide preclinical data for the development of pro-ABCA1 and/or anti-SR-B1 PCa therapies.
of Public Health Relevance Elucidating how HDL drives proliferative events in prostate cancer (PCa) is important for the design of interventional treatments for early-stage prostate cancer and preventative therapeutics for castration-resistant prostate cancer (CRPC). The proposed research will study the effects of ABCA1-mediated HDL biogenesis and SR-B1-mediated HDL uptake on PCa proliferation.
