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Programmed cell death during regression of PC-82 human prostate cancer following androgen ablation
N Kyprianou1, H F English, J T Isaacs
1Johns Hopkins Oncology Center, Baltimore, Maryland 21205.
Abstract:
To study the mechanism of regression of human prostatic cancer following androgen ablation, the androgen-responsive PC-82 human prostatic adenocarcinoma xenograft was used as a model system. Castration of male nude mice bearing PC-82 xenografts results in a 50% tumor regression by 2 wk following androgen ablation. This regression is due to a sequence of biochemical and morphological events that results in both the cessation of cell proliferation and activation of programmed death or apoptosis of the androgen-dependent prostatic cancer cells. Associated with this response are an enhanced expression of the transforming growth factor beta 1 gene, a potent inhibitor of cell proliferation, and testosterone-repressed prostatic message 2 (designated TRPM-2), a programmed cell death-associated gene. Fragmentation of tumor DNA into nucleosomal oligomers and histological appearance of apoptotic bodies are characteristic early events that preceded the dramatic reduction in tumor volume following androgen ablation. These results suggest that androgen-dependent human prostatic cancer cells, like normal prostatic cells, retain the ability to inhibit proliferation and to activate programmed cell death in response to androgen ablation. Clarification of the biochemical pathway involved in the activation of this programmed cell death should identify new targets of therapy for even androgen-independent human prostatic cancer.
Insights
Androgen ablation in human prostate cancer xenografts triggers tumor regression by halting cell growth and initiating programmed cell death (apoptosis). This involves key gene expressions, offering potential therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Human prostatic adenocarcinoma xenografts (PC-82) are used to model androgen-dependent prostate cancer.
- Androgen ablation is a standard treatment for prostate cancer, but its precise regression mechanisms require further elucidation.
Purpose of the Study:
- To investigate the molecular and cellular mechanisms driving tumor regression in androgen-dependent prostate cancer after androgen ablation.
- To identify key genes and pathways involved in programmed cell death (apoptosis) during cancer regression.
Main Methods:
- Utilized the androgen-responsive PC-82 human prostatic adenocarcinoma xenograft model in male nude mice.
- Performed castration to induce androgen ablation and monitored tumor volume changes.
- Analyzed biochemical and morphological changes, including gene expression (transforming growth factor beta 1, TRPM-2) and DNA fragmentation.
Main Results:
- Castration led to a 50% regression of PC-82 xenografts within 2 weeks.
- Tumor regression was characterized by suppressed cell proliferation and activated apoptosis.
- Enhanced expression of transforming growth factor beta 1 and testosterone-repressed prostatic message 2 (TRPM-2) genes was observed.
- Early events included DNA fragmentation and the formation of apoptotic bodies.
Conclusions:
- Androgen-dependent prostate cancer cells, similar to normal cells, undergo apoptosis upon androgen withdrawal.
- The study highlights the role of apoptosis in prostate cancer regression following androgen ablation.
- Understanding these pathways may reveal novel therapeutic targets for both androgen-dependent and -independent prostate cancers.