Role of TGF-β1/Smad3-mediated fibrosis in drug resistance mechanism of prolactinoma

Prolactinomas are the most common functional pituitary adenomas. While dopamine agonists are a primary method of therapeutic treatment, the rate of resistance to these drugs continues to increase each year. During previous long-term clinical investigations, we found that partial resistant prolactinomas exhibited significantly more fibrosis than did sensitive adenomas, suggesting a role of fibrosis in their drug resistance. Furthermore, resistant adenomas with extensive fibrosis mainly express type I and type III collagens. Since TGF-beta 1 is the key factor in the initiation and development of tissue fibrosis, including in the pituitary, in this study, we aimed to determine whether TGF-beta 1 mediated fibrosis in prolactinomas and whether fibrosis was related to prolactinoma drug resistance. Using immunochemistry and western blotting, we found that the TGF-beta 1/Smad3 signaling pathway-related proteins were elevated in resistant prolactinoma specimens with high degrees of fibrosis compared to levels in sensitive samples, suggesting that this pathway may play a role in prolactinoma fibrosis. In vitro, TGF-beta 1 stimulation promoted collagen expression in normal HS27 fibroblasts. Furthermore, the sensitivity of rat prolactinoma MMQ cells to bro-mocriptine decreased when they were co-cultured with HS27 cells treated with TGF-beta 1. The TGF-beta 1 Smad3 signaling-specific inhibitor SB431542 counteracted these effects, indicating that TGF-beta 1/Smad3-mediated fibrosis was involved in the drug-resistant mechanisms of prolactinomas. These results indicate that SB431542 may serve as a promising novel treatment for preventing fibrosis and further improving the drug resistance of prolactinomas. (C) 2018 Elsevier B.V. All rights reserved.