The inhibitory effects of gossypol on human prostate cancer cells-PC3 are associated with transforming growth factor beta1 (TGFbeta1) signal transduction pathway.
BACKGROUND
Racemic gossypol [(+/-)-GP], a naturally occurring polyphenolic yellow pigment present in cottonseed products, inhibits in vitro proliferation of Dunning prostate cancer cells (MAT-LyLu), human prostate cancer cells derived from a bone marrow metastasis (PC3), MCF-7 and primary cultured human prostate cells. (+/-)-GP also has the ability to inhibit the metastasis of lung and lymph nodes of the androgen-independent rodent prostate cancer cell line, MAT-LyLu, after implantation into Copenhagen rats.


METHODS
The effects of (+/-)-GP on the proliferation of human prostate cancer PC3 cells were determined by thymidine incorporation assay and doubling-time (DT) determination. The mechanisms of action of (+/-)-GP on the proliferation of PC3 cells were determined by RT-PCR analysis, ELISA assay and Western blot analysis.


RESULTS
The results show that (+/-)-GP caused reductions in DNA synthesis and prolonged the DTs in PC3 cells. RT-PCR and ELISA results show that (+/-)-GP elevate the mRNA expression and protein secretion of transforming growth factor beta1 (TGFbeta1) in PC3 cells. Consistent with these findings, (+/-)-GP has been shown to decrease the cyclin D1 mRNA expression and protein expression in PC3 cells. Furthermore, the growth inhibition of PC3 cells by conditioned media collected from the (+/-)-GP-treated-PC3 cells was completely reversed by addition of 25 microg/ml of mouse monoclonal anti-TGFbeta1, -beta2, -beta3 antibody, suggesting the involvement of TGFbeta1 in (+/-)-GP-induced growth inhibition of PC3 cells.


CONCLUSIONS
These results indicate that the inhibitory effects of (+/-)-GP on the proliferation of human prostate cancer PC3 cells are associated with induction of TGFbeta1, which in turn influences the expression of the cell cycle-regulatory protein, cyclin D1, in prostate cancer cells.
Jiang
Jiahua
J
Laboratory of Reproductive and Molecular Endocrinology, College of Veterinary Medicine, The Ohio State University, 1900 Coffey Road, Columbus, OH 43210, USA.
Sugimoto
Yasuro
Y
Liu
Suling
S
Chang
Hsiang-Lin
HL
Park
Kah-Young
KY
Kulp
Samuel K
SK
Lin
Young C
YC
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000187:drug effects; D006072:Gossypol / Q000494:pharmacology*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D023041:Xenograft Model Antitumor Assays
D012333:RNA, Messenger; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D019938:Cyclin D1; D006072:Gossypol