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

Abstract

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-β1 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-β1 mediated fibrosis in prolactinomas and whether fibrosis was related to prolactinoma drug resistance. Using immunochemistry and western blotting, we found that the TGF-β1/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-β1 stimulation promoted collagen expression in normal HS27 fibroblasts. Furthermore, the sensitivity of rat prolactinoma MMQ cells to bromocriptine decreased when they were co-cultured with HS27 cells treated with TGF-β1. The TGF-β1/Smad3 signaling-specific inhibitor SB431542 counteracted these effects, indicating that TGF-β1/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.

• Authors: Bin Hu, Zhigang Mao, Xiaobing Jiang, Dongsheng He, Zongming Wang, Xin Wang, Yonghong Zhu, Haijun Wang
• Journal: Brain research (Brain Res) Vol. 1698 Pg. 204-212 (11 01 2018) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 30055965 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• 4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
• Benzamides
• Dioxoles
• Dopamine Agonists
• SMAD3 protein, human
• Smad3 Protein
• TGFB1 protein, human
• Transforming Growth Factor beta1

Topics

• Adult
• Benzamides (pharmacology)
• Cell Line
• Dioxoles (pharmacology)
• Dopamine Agonists (pharmacology)
• Drug Resistance
• Female
• Fibroblasts (metabolism, pathology)
• Fibrosis (metabolism, pathology)
• Humans
• Male
• Middle Aged
• Pituitary Gland (metabolism, pathology)
• Pituitary Neoplasms (metabolism)
• Prolactinoma (drug therapy, metabolism, pathology)
• Smad3 Protein (metabolism)
• Transforming Growth Factor beta1 (metabolism)