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Programmed Death of Nonproliferating Androgen-independent Prostatic Cancer Cells¹

The Johns Hopkins Oncology Center [P. M., N. K., R. W. T., J. T. I.], James Buchanan Brady Urological Institute, and the Department of Urology [J. T. I.], Johns Hopkins School of Medicine, Baltimore, Maryland 21205

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⁺ (Ca₁). 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 Ca₁ 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 Ca₁ 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 Ca₁. These studies demonstrated that an elevation of Ca₁ 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 Ca₁ is sustained for a sufficient time. These observations identify Ca₁ as a potential target for therapy for androgen-independent prostatic cancer cells.

¹ Supported by NIH Grant CA50601. Partly supported by National Cancer Institute Grant 5-P30-CA06973.

² P. M. was a Fogarty Fellow supported by Grant FOSTW04050 during these studies. Present address: Department of Pathology, University of Turku, SF-20520, Finland.

³ Present address: Division of Urology, University of Maryland, 22 S. Greene Street, Baltimore, MD 21201.

⁴ To whom requests for reprints should be addressed, at 422 N. Bond Street, Baltimore, MD 21231.

Received 3/18/91. Accepted 6/25/91.

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