Regulation of Calcium Fluxes and Apoptosis by BCL-2 Family Proteins in Prostate Cancer Cells

摘要

Members of the BCL-2 family of cell death regulators play critical roles in the progression of androgen-independent, metastatic prostate cancer. Despite years of research, the molecular mechanisms underlying the effects of these proteins remain unclear. In previous studies we demonstrated that BCL-2 family proteins regulate a crucial step in the apoptotic pathway (cytochrome c release) by regulating endoplasmic reticular and mitochondrial calcium fluxes. In this project we are studying these effects in more detail, focusing on the possibility that the so-called 'BH3 only' proteins and Bax directly promote endoplasmic reticular calcium release. To this end, we are (1) Defining the effects of mitochondrial calcium uptake on cytochrome c mobilization and release; (2) Determining the effects of BH3 only members of the BCL-2 family on intracellular calcium fluxes; and (3) Identifying possible direct effects of Bax and Bak on ER calcium fluxes. With this information in hand, we expect that we will be able to define therapeutic strategies that directly target the cell death resistance mechanisms that appear to limit the effects of currently available therapies.