PROGRAMMED DEATH OF NONPROLIFERATING ANDROGEN-INDEPENDENT PROSTATIC-CANCER CELLS

Androgen ablation induces an energy-dependent process of programmed death in nonproliferating androgen-dependent prostatic cancer cells which involves fragmentation of genomic DNA into nucleosomal oligomers catalyzed by nuclear Ca2+, Mg2+-dependent endonuclease enzymes activated following a sustained elevation in intracellular free Ca2+ (Ca(i)). In contrast, androgen-independent prostatic cancer cells are not induced to undergo such programmed cell death by androgen ablation. One explanation for the inability of androgen ablation to induce programmed death of androgen-independent prostatic cancer cells is that such ablation does not result in a sustained elevation in Ca(i) in these cells. This raises the issue of whether androgen-independent prostatic cancer cells can be induced to undergo programmed death if an elevation in the Ca(i) is sufficiently sustained by nonhormonal means. To test this possibility, androgen-independent, highly metastatic Dunning R-3327 AT-3 rat prostatic cancer cells were chronically exposed in vitro to the calcium ionophore ionomycin to sustain an elevation in their Ca(i). These studies demonstrated that an elevation of Ca(i) as small as only 3-6-fold above baseline can induce the death of these cells if sustained for > 12 h. Temporal analysis demonstrated that the death of these cells does not require cell proliferation and involves Ca2+-induced fragmentation of genomic DNA into nucleosome-sized pieces as the commitment step in this process. These results demonstrate that even nonproliferating androgen-independent prostatic cancer cells can be induced to undergo programmed cell death if a modest elevation in the Ca(i) is sustained for a sufficient time. These observations identify Ca(i) as a potential target for therapy for androgen-independent prostatic cancer cells.