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Interactive Effects of Triiodothyronine and Androgens on Prostate Cell Growth and Gene Expression¹

Departments of Urology (S.Z., M.-L.H., W.Z., D.J.T., C.Y.F.Y.) and Biochemistry and Molecular Biology (D.J.T., C.Y.F.Y.), Laboratory Medicine and Pathology (G.G.K.), Mayo Graduate School, Mayo Clinic/Foundation, Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Charles Y. F. Young, Mayo Clinic/Foundation, 200 First Street, Southwest, Rochester, Minnesota 55905.

T₃ plays an important role in the regulation of cell growth and differentiation. In this study, we show the interactive effects of T₃ and androgens on the growth response and expression of the prostate-specific genes, PSA (prostate-specific antigen) and hK2 (human glandular kallikrein), in the human prostate cancer cell line, LNCaP. T₃ alone showed pronounced growth enhancement in a dose-dependent fashion. However, in the presence of androgens, higher concentrations of T₃ were required to produce additional proliferative effects. T₃, androgens, or a combination of the two up-regulated PSA protein production in a dose-dependent fashion, but T₃ had little stimulatory effect on hK2 protein expression, regardless of the presence or absence of androgens.

Using gene transfer assays, T₃ alone showed no effect on transcriptional activation of a reporter gene mediated by the PSA or hK2 enhancer/promoters. T₃ potentiated the androgen-mediated transcription of the PSA gene but not that of the hK2 gene. A previous study suggested that the T₃ effect on PSA protein expression was caused by an up-regulation of the androgen receptor (AR) protein by T₃. Our results contradict these. Although AR expression was increased by T₃ alone, Western blot analysis showed that the total cellular AR level was not further increased by T₃ in the presence of androgens, in comparison with cells stimulated by androgens alone. Both Western blot analysis and a gel DNA band shift assay revealed that nuclear AR was not increased by T₃. This study suggests that transcription factor(s) other than the AR may mediate T₃ enhancement of androgenic induction of PSA expression.

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