Increased TGF-β1-mediated suppression of growth and motility in castrate-resistant prostate cancer cells is consistent with Smad2/3 signaling

BACKGROUND Elevated TGF‐β levels are associated with prostate cancer progression. Although TGF‐β is a tumor suppressor for normal epithelial and early‐stage cancer cells, it may act paradoxically as a tumor promoter in more advanced cancers, although its effects are largely cell and context dependen...

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Published in:	The Prostate Vol. 72; no. 12; pp. 1339 - 1350
Main Authors:	Miles, Fayth L., Tung, Navpreet S., Aguiar, Adam A., Kurtoglu, Senem, Sikes, Robert A.
Format:	Journal Article
Language:	English
Published:	Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-09-2012 Wiley-Liss
Subjects:	Active Transport, Cell Nucleus - physiology androgen-sensitive Biological and medical sciences castrate-resistant cell cycle regulation Cell Line, Tumor Cell Movement - physiology Cell Proliferation growth Growth Inhibitors - physiology Gynecology. Andrology. Obstetrics Humans invasion Male Male genital diseases Medical sciences motility Nephrology. Urinary tract diseases Orchiectomy Phosphorylation - physiology prostate cancer Prostatic Neoplasms - pathology Prostatic Neoplasms - therapy Signal Transduction - physiology Smad2 Protein - physiology Smad3 Protein - physiology TGF-β1 Transforming Growth Factor beta1 - physiology Tumors Tumors of the urinary system Up-Regulation - physiology Urinary tract. Prostate gland Andrology Nephrology Smad protein Motility Prostate disease Growth Suppression Metastasis Signal transduction Regulation(control) androgen-sensitive Cell cycle Male genital diseases Tumor cell Urinary system disease Androgen Gynecology Malignant tumor Invasion Resistance castrate-resistant TGF-β1 Transforming growth factor β1 Sex steroid hormone cell cycle regulation Prostate cancer Cancer
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Summary:	BACKGROUND Elevated TGF‐β levels are associated with prostate cancer progression. Although TGF‐β is a tumor suppressor for normal epithelial and early‐stage cancer cells, it may act paradoxically as a tumor promoter in more advanced cancers, although its effects are largely cell and context dependent. This study analyzed prostate cancer responses to TGF‐β signaling in an isogenic model of androgen‐sensitive and castration‐resistant prostate cancer cells. METHODS Phosphorylation and nuclear translocation of Smad2 and Smad3 were analyzed using immunoblotting. Proliferation and cell cycle responses to TGF‐β1 (5 ng/ml) were assessed using growth assays and flow cytometry for DNA content, as well as Western blot and immunoprecipitation of cell cycle proteins. RESULTS Both androgen‐sensitive (LNCaP) and castration‐resistant (C4‐2 and C4‐2B) prostate cancer cell lines demonstrated TGF‐β1‐induced phosphorylation and nuclear translocation of Smad2/3 that was robust in metastatic lines. Smad phosphorylation was completely abrogated with inhibition of ALK‐5 kinase activity using the kinase inhibitor, SB‐431542. Increased sensitivity to TGF‐β1‐mediated growth inhibition was observed in C4‐2 and C4‐2B cells, as compared to LNCaP cells. This was paralleled with downregulation of Cyclin D and increased association of p15Ink4b or p27Kip with CDK's. Additionally, TGF‐β1 inhibited motility and invasion of metastatic cell lines. CONCLUSIONS TGF‐β‐mediated suppression of growth and motility is enhanced in metastatic, castration‐resistant prostate cancer cells. Enhanced TGF‐β1‐induced Smad2 and ‐3 signaling in prostate cancer cells may correlate with tumor suppressive activity. Therefore, the direct effects of TGF‐β1 on prostate cancer cells post‐castration may be anti‐tumorigenic and growth‐suppressive. Prostate 72:1339–1350, 2012. © 2012 Wiley Periodicals, Inc.
Bibliography:	ArticleID:PROS22482 ark:/67375/WNG-ZTKNC8BX-7 istex:30F0027AE88E513A0A5FA99741A653373B44EFBB ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0270-4137 1097-0045
DOI:	10.1002/pros.22482