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 engineer ed to overproduce transforming growth factor beta 1 (TGF beta 1) produ ce larger, more metastatic tumors in vivo. We recognized that this abi lity of TGF beta 1 to act as a positive modulator of prostate tumor be havior 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 cyc lase (AC)-cAMP pathway is affected. TGF beta 1- overproducing cells ha d lower membrane AC activity, lower intracellular cAMP content, and a lower G(s 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 t he 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 inhi bitor cAMP. Therefore, TGF beta 1 overproduction could affect tumor be havior in vivo in part via a direct effect on the tumor cells.