Effects of transforming growth factor beta 1 on the adenylyl cyclase-cAMP pathway in prostate cancer.
We reported previously that MATLyLu rat prostate cancer cells engineered to overproduce transforming growth factor beta 1 (TGF beta 1) produce larger, more metastatic tumors in vivo. We recognized that this ability of TGF beta 1 to act as a positive modulator of prostate tumor behavior might be due to effects of TGF beta 1 on the host and/or on the tumor cells. In this study we demonstrated that the cells themselves respond to endogenously produced TGF beta 1, and that the adenylyl cyclase (AC)-cAMP pathway is affected. TGF beta 1-overproducing cells had lower membrane AC activity, lower intracellular cAMP content, and a lower Gs alpha protein level than did control cells. Prostate cancer cells were growth inhibited by 8-bromo-cAMP or forskolin, agents that elevate intracellular cAMP. Thus, TGF beta 1 overproduction affects the phenotype of the tumor cells, deliberate activation of endogenously produced latent TGF beta 1 is not required (indicating that the cells themselves are capable of activating latent TGF beta 1), and TGF beta 1 overproduction lowers the cellular concentration of the growth inhibitor cAMP. Therefore, TGF beta 1 overproduction could affect tumor behavior in vivo in part via a direct effect on the tumor cells.
Steiner
M S
MS
Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Wand
G S
GS
Barrack
E R
ER
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000378:metabolism*; D051381:Rats; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D016212:Transforming Growth Factor beta; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases