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Programmed death of nonproliferating androgen-independent prostatic cancer cells
P Martikainen1, N Kyprianou, R W Tucker
1Johns Hopkins Oncology Center, Johns Hopkins School of Medicine, Baltimore, Maryland 21205.
Abstract:
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+, Mg(2+)-dependent endonuclease enzymes activated following a sustained elevation in intracellular free Ca2+ (Cai). 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 Cai 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 Cai 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 Cai. These studies demonstrated that an elevation of Cai as small as only 3-6-fold above baseline can induce the death of these cells if sustained for greater than 12 h. Temporal analysis demonstrated that the death of these cells does not require cell proliferation and involves Ca(2+)-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 Cai is sustained for a sufficient time. These observations identify Cai as a potential target for therapy for androgen-independent prostatic cancer cells.
Insights
Sustained elevation of intracellular calcium (Cai) can induce programmed cell death in androgen-independent prostate cancer cells. This finding suggests Cai is a potential therapeutic target for advanced prostate cancer.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Androgen ablation triggers programmed cell death in androgen-dependent prostate cancer cells via calcium-mediated DNA fragmentation.
- Androgen-independent prostate cancer cells resist this programmed cell death, as androgen ablation does not sustain intracellular calcium (Cai).
Purpose of the Study:
- To investigate if sustained elevation of Cai, independent of hormonal manipulation, can induce programmed cell death in androgen-independent prostate cancer cells.
- To determine the threshold and duration of Cai elevation required to trigger cell death in these resistant cancer cells.
Main Methods:
- Androgen-independent Dunning R-3327 AT-3 rat prostate cancer cells were cultured in vitro.
- Cells were chronically exposed to the calcium ionophore ionomycin to achieve sustained elevation of intracellular free Ca2+ (Cai).
- Cell death and DNA fragmentation were analyzed over time.
Main Results:
- A sustained 3-6 fold increase in Cai above baseline for over 12 hours induced cell death in androgen-independent prostate cancer cells.
- Cell death occurred independently of cell proliferation and involved Ca2+-induced genomic DNA fragmentation into nucleosomal fragments.
- The commitment step in this process was the Ca2+-induced DNA fragmentation.
Conclusions:
- Nonproliferating, androgen-independent prostate cancer cells can be induced to undergo programmed cell death by sustaining a modest elevation in Cai.
- Intracellular calcium (Cai) represents a potential therapeutic target for treating androgen-independent prostate cancer.