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Expression of novel genes linked to the androgen-induced, proliferative shutoff in prostate cancer cells
1Department of Anatomy and Cell Biology, Tufts University School of Medicine, Boston, MA 02111, USA.
Abstract:
Androgens control cell numbers in the prostate through three separate pathways: (a) inhibition of cell death, (b) induction of cell proliferation (Step-1) and (c) inhibition of cell proliferation (Step-2, proliferative shutoff). The mechanisms underlying these phenomena are incompletely understood. The human prostate carcinoma LNCaP variants express these pathways as follows: LNCaP-FGC express both steps, LNCaP-LNO expresses Step-2, LNCaP-TAC expresses Step-1, and LNCaP-TJA cells express neither step. These cells facilitated the search for mediators of the androgen-induced proliferative shutoff pathway. Androgen exposure for 24 h or longer induced an irreversible proliferative shutoff in LNCaP-FGC cells. The Wang and Brown approach for identifying differentially expressed mRNAs was used to search for mediators of Step-2. Ten unique inserts were identified and from those ten, three genes were further studied. The basal expression of these genes in shutoff-negative variants was not affected by androgen exposure. They were induced by androgens in shutoff-positive LNCaP variants and the androgen receptor-transfected, shutoff-positive, MCF7-AR1 cells. These genes were induced only in the range of androgen concentrations that elicited the shutoff response. Time course analysis showed that their induction precedes the commitment point by 12-18 h. In addition, they were expressed in the normal prostate during proliferative shutoff. These features suggest that the candidate genes have a role in the regulation cascade for proliferative shutoff.
Insights
Researchers identified key genes mediating androgen-induced prostate cell proliferation shutoff. These genes are activated by androgens, preceding the shutoff, and are present in normal prostate tissue during this process.
Area of Science:
- Molecular Endocrinology
- Prostate Cancer Biology
Background:
- Androgens regulate prostate cell numbers via distinct pathways, including proliferation and cell death.
- The mechanisms of androgen-driven proliferative shutoff (Step-2) are not fully understood.
- LNCaP prostate cancer cell variants exhibit differential expression of these androgen-responsive pathways.
Purpose of the Study:
- To identify novel mediators of the androgen-induced proliferative shutoff pathway in prostate cells.
- To characterize the role of candidate genes in the regulation of prostate cell proliferation.
Main Methods:
- Utilized LNCaP prostate carcinoma cell variants with defined androgen pathway expression.
- Employed the Wang and Brown approach to identify differentially expressed messenger RNAs (mRNAs).
- Analyzed gene expression in response to androgen exposure, concentration, and time course.
Main Results:
- Identified three candidate genes induced by androgens specifically in androgen-responsive, shutoff-positive cells.
- Androgen induction of these genes occurred within the concentration range that triggers proliferative shutoff.
- Gene induction preceded the proliferative shutoff commitment point by 12-18 hours and was observed in normal prostate tissue.
Conclusions:
- The identified candidate genes are likely involved in the regulatory cascade of androgen-induced prostate cell proliferative shutoff.
- These genes represent potential therapeutic targets for modulating prostate cell growth.
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