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Mullerian Inhibiting Substance Regulates Androgen-Induced Gene Expression and Growth in Prostate Cancer Cells through a Nuclear Factor-B-Dependent Smad-Independent Mechanism

Department of Surgical Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Dr. Shyamala Maheswaran, Jackson 904, Surgical Oncology, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114. E-mail: maheswaran{at}helix.mgh.harvard.edu.

Mullerian inhibiting substance (MIS), a member of the TGFß superfamily, causes regression of the Mullerian duct in male embryos. The presence of MIS type II and type I receptors in tissues and cell lines derived from the prostate suggests that prostate is a likely target for MIS. In this report, we demonstrate that MIS inhibits androgen-stimulated growth of LNCaP cells and decreases their survival in androgen-deprived medium by preventing cell cycle progression and inducing apoptosis. Expression of dominant-negative Smad1 reversed the ability of MIS to decrease LNCaP cell survival in androgen-deprived medium but not androgen-stimulated growth, whereas abrogation of nuclear factor-B (NFB) activation ablated the suppressive effects of MIS on both androgen-stimulated growth and androgen-independent survival. The effect of MIS on androgen-induced growth was not due to changes in androgen receptor expression. However, MIS suppressed androgen-stimulated transcription of prostate-specific antigen; ablation of NFB activation reversed MIS-mediated suppression of prostate-specific antigen. These observations suggest that MIS regulates androgen-induced gene expression and growth in prostate cancer cells through a NFB-dependent but Smad1-independent mechanism. Thus, MIS, in addition to potentially regulating prostate growth indirectly by suppressing testicular testosterone synthesis, may also be a direct regulator of androgen-induced gene expression and growth in the prostate at the cellular level.

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Ligands:   R1881

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