Hormone-regulated Apoptosis Results from Reentry of Differentiated Prostate Cells onto a Defective Cell Cycle1

Castration initiates extensive apoptosis of the secretory epithelial cells lining the ducts of the rat ventral prostate, resulting in the striking regression of this male sexual accessory tissue. We had previously described the paradox of finding similar cascades of gene activity (c-fos > c-myc > hsp-70) induced during the early period of ventral prostate regression and during the regrovrth of the ventral prostate gland initi ated by testosterone replenishment. This common pattern of protoon cogene expression during periods of predominant cellular apoptosis or proliferation caused us to examine further the possibility that the two cellular events occur through identical early molecular pathways. In the present study we demonstrate that apoptotic prostate epithelial cells incorporate bromodeoxyuridine into nuclear high-molecular-weight DNA prior to nuclear DNA fragmentation. The DNA synthetic activityoccurs in coordination with a massive induction of proliferai ivo cell nuclear antigen, a proliferation marker, in the nuclei of androgen-deprived prostatic epithelial cells. Moreover, this activity is also associ ated with the increased expression of mRNA encoding p53, a suppressor gene well known as a cell cycle-blocking agent. Our data indicate that quiescent (G0) prostate epithelial cells undergo apoptosis due to two sequential events initiated by testosterone depletion. The first event is the active reentry of these cells into the cell cycle. The second event is the apoptotic destruction resulting from the inability of the differenti ated cells to successfully complete this cycle.