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Treatment with antiandrogens induces an androgen-repressed gene in the rat ventral prostate
J G Léger1, R Le Guellec, M P Tenniswood
1Department of Biochemistry, University of Ottawa, Ontario, Canada.
Abstract:
We have recently described an androgen-repressed gene in the rat ventral prostate, termed TRPM-2, that appears to be involved in the processes of cell regression and programmed cell death. We have analyzed the effect of two antiandrogens currently used in the treatment of prostatic carcinoma on the induction of this gene. Cyproterone acetate (10 mg/day) and flutamide (15 mg/day), when administered to castrated rats receiving a maintenance dose of 5 alpha-dihydrotestosterone proprionate (250 micrograms/day), induce the expression of TRPM-2. Northern hybridization and dot blot analysis demonstrate that TRPM-2 steady-state levels reach a maximum on day 4 of treatment with cyproterone acetate (520 ppm) and on day 6 of treatment with flutamide (190 ppm). During this time the steady-state levels of the androgen-dependent prostate steroid-binding protein mRNA are reduced dramatically (from approximately 75,000 to 10,000 ppm), but are not eliminated even after extended treatment. Treatment with the two antiandrogens produces a substantial reduction in the organ weight/body weight ratio and RNA content of the prostate when compared to rats receiving the maintenance dose alone. These results suggest that while neither cyproterone acetate nor flutamide fully repress the androgen-dependent functions of the prostate, they do induce some of the androgen-repressed sequences in the prostate that have been implicated in the process of cell death.
Insights
Two antiandrogens, cyproterone acetate and flutamide, induce the TRPM-2 gene in rat prostates, a key factor in programmed cell death. This suggests a role for TRPM-2 in antiandrogen therapy for prostate cancer.
Area of Science:
- Molecular Endocrinology
- Cancer Biology
- Prostate Cancer Research
Background:
- The TRPM-2 gene is androgen-repressed and implicated in prostate cell regression.
- Antiandrogens are used in treating prostatic carcinoma.
Purpose of the Study:
- To analyze the effect of cyproterone acetate and flutamide on TRPM-2 gene induction.
- To investigate the impact of these antiandrogens on prostate gene expression and tissue characteristics.
Main Methods:
- Administration of antiandrogens (cyproterone acetate, flutamide) to castrated rats receiving testosterone.
- Northern hybridization and dot blot analysis to quantify TRPM-2 and prostate steroid-binding protein mRNA levels.
- Measurement of prostate organ weight and RNA content.
Main Results:
- Both cyproterone acetate and flutamide induced TRPM-2 gene expression, peaking on days 4 and 6, respectively.
- Androgen-dependent prostate steroid-binding protein mRNA levels decreased significantly but were not fully eliminated.
- Antiandrogen treatment reduced prostate weight/body weight ratio and RNA content.
Conclusions:
- Cyproterone acetate and flutamide induce androgen-repressed genes like TRPM-2 in the prostate.
- These antiandrogens initiate processes associated with cell death, despite not fully repressing all androgen-dependent functions.
- TRPM-2 induction may be a significant mechanism in antiandrogen therapy for prostate cancer.