Mutually antagonistic effects of androgen and activin in the regulation of prostate cancer cell growth.
Activin, a member of the TGFbeta superfamily, is expressed in the prostate and inhibits growth. We demonstrate that the effects of activin and androgen on regulation of prostate cancer cell growth are mutually antagonistic. In the absence of androgen, activin induced apoptosis in the androgen-dependent human prostate cancer cell line LNCaP, an effect suppressed by androgen administration. Although activin by itself did not alter the cell cycle distribution, it potently suppressed androgen- induced progression of cells into S-phase of the cell cycle and thus inhibited androgen-stimulated growth of LNCaP cells. Expression changes in cell cycle regulatory proteins such as Rb, E2F-1, and p27 demonstrated a strong correlation with the mutually antagonistic growth regulatory effects of activin and androgen. The inhibitory effect of activin on growth was independent of serine, serine, valine, serine motif phosphorylation of Smad3. Despite their antagonistic effect on growth, activin and androgen costimulated the expression of prostate-specific antigen through a Smad3-mediated mechanism. These observations indicate the existence of a complex cross talk between activin and androgen signaling in regulation of gene expression and growth of the prostate.
Carey
Jennifer L
JL
Pediatric Surgical Research Laboratories, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
Sasur
Laura M
LM
Kawakubo
Hirofumi
H
Gupta
Vandana
V
Christian
Benjamin
B
Bailey
Paul M
PM
Maheswaran
Shyamala
S
D028341:Activins / Q000378:metabolism* / Q000494:pharmacology; D000728:Androgens / Q000378:metabolism* / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D006801:Humans; D028322:Inhibin-beta Subunits / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D010766:Phosphorylation; D017430:Prostate-Specific Antigen / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D016160:Retinoblastoma Protein / Q000187:drug effects / Q000378:metabolism; D016196:S Phase / Q000187:drug effects / Q000502:physiology; D051900:Smad3 Protein; D015534:Trans-Activators / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000187:drug effects / Q000378:metabolism
D000728:Androgens; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D016160:Retinoblastoma Protein; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C422405:activin A; D028341:Activins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D028322:Inhibin-beta Subunits; D017430:Prostate-Specific Antigen