The role of TGF-β/Smad signaling in dopamine agonist-resistant prolactinomas.

Abstract

BACKGROUND:

Prolactinomas are the most common secretory pituitary adenomas. The first line of treatment involves dopamine agonists (DAs); however, a subset of patients is resistant to such therapy. Recent studies suggest that dopamine can up-regulate TGF-β1 synthesis in rat pituitary lactotrophs whereas estradiol down-regulates TGF-β1. To date, the role of TGF-β/Smad signaling in DAs-resistant prolactinomas has not been explored.

METHODS:

High-content screening (HCS) techniques, qRT-PCR, Western blot, immunofluorescence and ELISA, were performed to determine the role of TGF-β/Smad signaling in DAs-resistant prolactinomas.

RESULTS:

We reported a significant down-regulation of TGF-β/Smad signaling cascade in DAs-resistant prolactinomas compared to normal human anterior pituitaries. Following treatment with TGF-β1, the dopamine agonist, bromocriptine, and the estrogen antagonist (ER), fulvestrant in GH3 cells, we found that TGF-β1 and fulvestrant caused significant cytotoxicity in a dose- and time-dependent manner and activated Smad3 was detected following exposure to TGF-β1 and fulvestrant. In addition, treating GH3 cells with fulvestrant increased active TGF-β1 levels and decreased PRL levels in a dose-dependent manner.

CONCLUSION:

TGF-β/Smad signaling pathway may play an important role in DA-resistant prolactinomas and has the potential to be a viable target for the diagnosis and treatment of prolactinomas, particularly in patients who are resistant to DAs.

• Authors: Zhenye Li, Qian Liu, Chuzhong Li, Xuyi Zong, Jiwei Bai, Youtu Wu, Xiaolei Lan, Guoqiang Yu, Yazhuo Zhang
• Journal: Molecular and cellular endocrinology (Mol Cell Endocrinol) Vol. 402 Pg. 64-71 (Feb 15 2015) ISSN: 1872-8057 [Electronic] Ireland
• PMID: 25578603 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Dopamine Agonists
• SMAD3 protein, human
• Smad3 Protein
• TGFB1 protein, human
• Transforming Growth Factor beta1
• Fulvestrant
• Bromocriptine
• Estradiol

Topics

• Adult
• Animals
• Antineoplastic Agents (pharmacology)
• Bromocriptine (pharmacology)
• Cell Line, Tumor
• Dopamine Agonists (pharmacology)
• Drug Resistance, Neoplasm
• Estradiol (analogs & derivatives, pharmacology)
• Female
• Fulvestrant
• Humans
• Male
• Middle Aged
• Phosphorylation
• Pituitary Neoplasms (drug therapy, metabolism)
• Prolactinoma (drug therapy, metabolism)
• Protein Processing, Post-Translational
• Rats
• Signal Transduction
• Smad3 Protein (metabolism)
• Transforming Growth Factor beta1 (metabolism)
• Young Adult