Mullerian inhibiting substance regulates androgen-induced gene expression and growth in prostate cancer cells through a nuclear factor-kappaB-dependent Smad-independent mechanism.
Mullerian inhibiting substance (MIS), a member of the TGFbeta 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-kappaB (NFkappaB) 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 NFkappaB 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 NFkappaB-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.
Tran
Trinh T
TT
Department of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Segev
Dorry L
DL
Gupta
Vandana
V
Kawakubo
Hirofumi
H
Yeo
Giminna
G
Donahoe
Patricia K
PK
Maheswaran
Shyamala
S
D000728:Androgens / Q000378:metabolism*; D054304:Anti-Mullerian Hormone; D017209:Apoptosis / Q000502:physiology; D015152:Blotting, Northern; D015153:Blotting, Western; D002453:Cell Cycle / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D008156:Luciferases; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000503:physiopathology; D051898:Smad1 Protein / Q000378:metabolism*; D013735:Testicular Hormones / Q000378:metabolism*
D000728:Androgens; D006023:Glycoproteins; D016328:NF-kappa B; C497399:SMAD1 protein, human; D051898:Smad1 Protein; D013735:Testicular Hormones; D054304:Anti-Mullerian Hormone; D008156:Luciferases; D017430:Prostate-Specific Antigen