Effects of transforming growth factor β1 on the adenylyl cyclase-cAMP pathway in prostate cancer

We reported previously that MATLyLu rat prostate cancer cells engineered to overproduce transforming growth factor β1 (TGFβ1) produce larger, more metastatic tumors in vivo. We recognized that this ability of TGFβ1 to act as a positive modulator of prostate tumor behavior might be due to effects of TGFβ1 on the host and/or on the tumor cells. In this study we demonstrated that the cells themselves respond to endogenously produced TGFβ1, and that the adenylyl cyclase (AC)-cAMP pathway is affected. TGFβ1-overproducing cells had lower membrane AC activity, lower intracellular cAMP content, and a lower G_sα protein level than did control cells. Prostate cancer cells were growth inhibited by 8-bromo-cAMP or forskolin, agents that elevate intracellular cAMP. Thus, TGFβ1 overproduction affects the phenotype of the tumor cells, deliberate activation of endogenously produced latent TGFβ1 is not required (indicating that the cells themselves are capable of activating latent TGFβ1), and TGFβ1 overproduction lowers the cellular concentration of the growth inhibitor cAMP. Therefore, TGFβ1 overproduction could affect tumor behavior in vivo in part via a direct effect on the tumor cells.