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Androgen regulation of programmed death of normal and malignant prostatic cells
J T Isaacs1, P I Lundmo, R Berges
1Johns Hopkins Oncology Center, Johns Hopkins Medical Institute, Baltimore, Maryland.
Abstract:
Androgen-dependent normal prostatic glandular cells and androgen-dependent prostatic cancer cells can be induced to undergo cell death after androgen ablation. This death does not require the cells to proliferate and occurs as an energy-dependent process collectively referred to as "programmed cell death" in which the cells actively commit "suicide." Associated with this programmed cell death pathway is the enhanced expression of a series of genes and the fragmentation of the genomic DNA into nucleosomal oligomers. This genomic DNA fragmentation is the irreversible commitment step in the death of the cell and results from activation of Ca2+/Mg(2+)-dependent endonuclease activity within the cell nucleus. This activation is due to sustained elevation of intracellular free Ca2+ (Cai) induced after androgen ablation. Metastatic prostatic cancer within an individual patient is heterogeneous, including both androgen-dependent and -independent cancer cells. Thus, androgen ablation is rarely curative since it only induces the programmed death of the androgen-dependent cancer cells without activating this pathway in the androgen-independent cancer cells within the patient. Androgen-independent prostatic cancer cells do not activate this death process after androgen ablation, since this does not induce a sustained increase in Cai. A new approach to treat androgen-independent prostatic cancer cells has focused on the use of chemotherapeutic agents to induce a sustained increase in Cai. These studies demonstrate that if such a sustained elevation in Cai is maintained, even androgen-independent prostatic cancer cells undergo programmed cell death.
Insights
Androgen ablation triggers programmed cell death in prostate cancer cells by increasing intracellular calcium (Cai). This method is effective for androgen-dependent cells but not independent ones, highlighting a new therapeutic strategy.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Androgen ablation induces programmed cell death in androgen-dependent prostate cancer cells.
- This process involves energy-dependent cell suicide and DNA fragmentation.
- A sustained increase in intracellular free calcium (Cai) is crucial for this cell death pathway.
Purpose of the Study:
- To investigate the mechanism of programmed cell death in prostate cancer.
- To explore therapeutic strategies for androgen-independent prostate cancer.
Main Methods:
- Analyzing gene expression and DNA fragmentation in response to androgen ablation.
- Measuring intracellular free calcium (Cai) levels in prostate cancer cells.
- Evaluating the efficacy of chemotherapeutic agents in inducing Cai elevation.
Main Results:
- Androgen ablation leads to programmed cell death in androgen-dependent cells via Cai elevation and DNA fragmentation.
- Androgen-independent cells do not undergo programmed cell death after androgen ablation due to lack of sustained Cai increase.
- Chemotherapeutic agents can induce sustained Cai elevation, triggering programmed cell death in androgen-independent prostate cancer cells.
Conclusions:
- Sustained elevation of intracellular free calcium (Cai) is a key mechanism for inducing programmed cell death in prostate cancer cells.
- Targeting Cai levels offers a potential therapeutic approach for androgen-independent prostate cancer.