Cell proliferation, DNA repair, and p53 function are not required for programmed death of prostatic glandular cells induced by androgen ablation.

Abstract

Androgen ablation induces programmed death of androgen-dependent prostatic gdular cells, resulting in fragmentation of their genomic DNA and the cells themselves into apoptotic bodies. Twenty percent of prostatic glandular cells undergo programmed death per day between day 2 and 5 after castration. During this same period, <1% of prostatic landular cells enter the S phase of the cell cycle, documenting that >95% of these die in Go. During the programmed death of these Go gadular cells, a futile DNA repir process is induced secondary to the DNA frentation. This futUle DNA repair is not required, however, since inhibition of this process by >90% with an appropriately timed hydroxyurea dosing regimen had no effect upon the extent of the prmme death ofthese cells after castration. Likewise, p53 gene expression is not required since the same degree of cell death occurred in prostates and seminal vesicles after castration of wlld-type and p53-deficient mice.Metastatic prostatic cancer is often highly responsive to androgen ablation therapy (1). After an initial response, unfortunately, relapse occurs due to the growth of androgenindependent prostatic cancer cells. This relapse occurs even if complete androgen blockage is used, and thus androgen ablation is rarely curative (2). The realization that the relapse is due to the continuing growth of androgen-independent prostatic cancer cells for which there is no effective therapy (3) has led to a search for new methods of controlling these cells. A lead for such an approach is based upon the understanding that the rapid involution of the normal prostate induced by androgen ablation is due to the activation of the process of cellular suicide, termed programmed cell death or apoptosis (4-6). Programmed death induced in the prostate is cell type specific. Only glandular epithelial cells and not basal epithelial cells or stromal cells are androgen dependent and thus undergo programmed cell death following castration (7). These glandular cells constitute :85% of the total cells in the ventral prostate ofan intact adult male rat, and 80%o ofthese glandular cells die within 1 week after castration (7). This is due to the activation of the programmed cell death pathway normally repressed by androgen in the prostate (7)(8)(9)(10)(11)(12)(13)(14)(15)(16). This programmed death pathway involves an energy-dependent cascade in which the cells undergo an epigenetic reprogramming, which leads to double-stranded fragmentation of their DNA followed by cellular fragmentation into apoptotic bodies (4, 6, 9, 12). These apoptotic bodies are then phagocytosized by either intraepithelial macrophages or other glandular cells (4,11,17

Why are epididymal tumours so rare?

“…24,25 Similarly low proliferation rates (1.3%) have been confirmed in the adult rat prostate. 26 It seems unlikely that proliferation rates alone can account for the far higher tumour incidence in the prostate than that of the epididymis. …”

Comparative alterations in p53 expression and apoptosis in the irradiated rat small and large intestine

“…Although some reports dispute the importance of p53 in apoptosis induced during certain physiological and pathological states (Berges et al, 1993;Clarke et al, 1993), there is now strong evidence for a positive link between expression of p53 and induction of apoptosis in many other instances (Donehower et al, 1992;Clarke et al, 1993;Lowe et al, 1993;Zhang et al, 1994). As well, wild-type p53, lately recognised as a 'guardian of the genome', regulates DNA replication and repair (Lane, 1992).…”

Cooperative therapeutic effects of androgen ablation and adenovirus-mediated herpes simplex virus thymidine kinase gene and ganciclovir therapy in experimental prostate cancer

“…In the normal rodent prostate, castration results in an induction of apoptosis within the glandular epithelium, with an 80% reduction in prostatic wt/wt by 10 days postcastration. 24 An examination of human prostate specimens after 3 months of androgen ablation also demonstrates an increase in apoptotic activity within both cancerous and noncancerous prostatic tissues. 25,26 Previous studies with androgen-sensitive MPR tumors have demonstrated androgen-sensitive activities in regard to both the growth and expression of apoptosis-related genes in response to castration in vivo.…”