TY - JOUR
T1 - Mullerian inhibiting substance regulates androgen-induced gene expression and growth in prostate cancer cells through a nuclear factor-κB-dependent smad-independent mechanism
AU - Tran, Trinh T.
AU - Segev, Dorry L.
AU - Gupta, Vandana
AU - Kawakubo, Hirofumi
AU - Yeo, Giminna
AU - Donahoe, Patricia K.
AU - Maheswaran, Shyamala
PY - 2006
Y1 - 2006
N2 - Mullerian inhibiting substance (MIS), a member of the TGFβ 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-κB (NFκB) 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 NFκB 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 NFκB-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.
AB - Mullerian inhibiting substance (MIS), a member of the TGFβ 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-κB (NFκB) 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 NFκB 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 NFκB-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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U2 - 10.1210/me.2005-0480
DO - 10.1210/me.2005-0480
M3 - Article
C2 - 16740653
AN - SCOPUS:33749338097
SN - 0888-8809
VL - 20
SP - 2382
EP - 2391
JO - Molecular Endocrinology
JF - Molecular Endocrinology
IS - 10
ER -