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The impact of bcl-2 expression and bax deficiency on prostate homeostasis in vivo
E M Bruckheimer1, S Cho, S Brisbay
1Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, TX 77030, USA.
Abstract:
Prostatic glandular epithelial cells undergo apoptosis in response to androgen-deprivation. The molecular determinants of androgen-responsiveness in these cells are incompletely understood. Recent evidence suggests that bcl-2 gene family members may be important in this context. We used the probasin promoter to target a human bcl-2 transgene specifically to the prostate in order to assess its impact on conferring resistance to androgen withdrawal in, otherwise sensitive, prostatic glandular epithelial cells in vivo. We examined the contribution of bax to mediating androgen-responsiveness in prostatic glandular epithelial cells using bax knockout mice. The histologic appearance of the prostates from probasin-bcl-2 transgenic mice or bax-/- mice did not differ from those of control littermates. There was no evidence of hyperplastic or neoplastic growth. There was no difference between probasin bcl-2 transgenic mice, bax-/- mice, and control littermates in steady-state levels of apoptosis. Following castration our findings suggest that both bax and bcl-2 may each contribute to the androgen-responsiveness of prostatic glandular epithelial cells. It is apparent from these results, however, that bax is not required to mediate cell death in prostatic glandular epithelial cells following castration. A comparison between the apoptotic indices in the ventral prostate from the probasin-bcl-2 and bax-/- mice following castration suggests that the presence of bcl-2 may be a more important indicator of androgen-sensitivity than a deficiency of bax.
Insights
Prostate cells undergo apoptosis when deprived of androgens. This study investigated the roles of bcl-2 and bax in this process, finding bcl-2 may be more crucial for androgen sensitivity than bax deficiency.
Area of Science:
- Molecular biology
- Cell biology
- Oncology
Background:
- Prostatic glandular epithelial cells undergo apoptosis upon androgen deprivation.
- The molecular mechanisms driving androgen responsiveness are not fully understood.
- Bcl-2 gene family members are implicated in this cellular response.
Purpose of the Study:
- To investigate the role of human bcl-2 transgene in conferring resistance to androgen withdrawal in prostatic cells.
- To examine the contribution of bax in mediating androgen responsiveness in prostatic glandular epithelial cells.
- To elucidate the molecular determinants of androgen-responsiveness in prostate cells.
Main Methods:
- Utilized probasin promoter to target a human bcl-2 transgene specifically to the prostate in vivo.
- Employed bax knockout mice to assess the contribution of bax.
- Analyzed prostatic histology and apoptosis levels in transgenic and knockout mice compared to controls.
- Examined steady-state and castration-induced apoptosis indices.
Main Results:
- No significant differences in prostate histology, hyperplasia, or neoplasia were observed between probasin-bcl-2 transgenic mice, bax knockout mice, and controls.
- Steady-state apoptosis levels were similar across all groups prior to castration.
- Following castration, both bax and bcl-2 appear to contribute to androgen responsiveness.
- Bax is not essential for mediating cell death in prostatic glandular epithelial cells post-castration.
- The presence of bcl-2 emerged as a more significant indicator of androgen sensitivity than bax deficiency.
Conclusions:
- Bcl-2 and bax play roles in the androgen-responsiveness of prostatic glandular epithelial cells.
- Bcl-2 may be a more critical factor in determining androgen sensitivity in prostate cells than bax.
- Further research into bcl-2 family members is warranted for understanding prostate cancer biology and therapeutic strategies.