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Submitted on November 29, 2005
Accepted on May 24, 2006
Department of Surgical Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114
* To whom correspondence should be addressed. E-mail: maheswaran{at}helix.mgh.harvard.edu.
Mullerian Inhibiting Substance, a member of the TGF
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 NFkB 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 (PSA); ablation of NFkB activation reversed MIS-mediated suppression of PSA. These observations suggest that MIS regulates androgen-induced gene expression and growth in prostate cancer cells through a NFkB-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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