2. Academic Validation
  3. Androgen Receptor Mediates Dopamine Agonist Resistance by Regulating Intracellular Reactive Oxygen Species in Prolactin-Secreting Pituitary Adenoma

Androgen Receptor Mediates Dopamine Agonist Resistance by Regulating Intracellular Reactive Oxygen Species in Prolactin-Secreting Pituitary Adenoma

  • Antioxid Redox Signal. 2025 Jun;42(16-18):954-972. doi: 10.1089/ars.2024.0611.
Linpeng Xu 1 2,  Zhuowei Lei 1 3,  Quanji Wang 1 2,  Qian Jiang 1 2,  Biao Xing 1 2,  Xingbo Li 1 2,  Xiang Guo 1 2,  Zihan Wang 1 2,  Sihan Li 1 2,  Yimin Huang 1 2,  Ting Lei 1 2
Affiliations

Affiliations

  • 1 Sino-German Neuro-Oncology Molecular Laboratory, Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.
  • 2 Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Department of Orthopedics, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.
PMID: 39360800 DOI: 10.1089/ars.2024.0611
Abstract

Aims: Dopamine agonists (DAs) are the first-line treatment for patients with prolactin-secreting pituitary adenoma (PRL adenoma). However, a subset of individuals exhibits poor responses, known as DA resistance. Previous studies have reported that DA resistance is more prevalent in male patients. This study aims to investigate the relationship between Androgen Receptor (AR) expression and DA resistance, as well as to explore underlying mechanisms of AR-mediated DA resistance. Results: Our results demonstrated that patients with higher AR expression exhibit greater resistance to DA in our cohort of DA-resistant PRL adenoma. Furthermore, AR was found to be involved in cell proliferation, PRL secretion, and resistance to bromocriptine (BRC) both in vitro and in vivo. Mechanistically, we demonstrated that intracellular Reactive Oxygen Species (ROS) function as upstream mediators of Apoptosis and Ferroptosis following BRC treatment. As a ligand-dependent transcription factor, AR could translocate to the nucleus and transcriptionally promote NFE2-like bZIP transcription factor 2 (NRF2) expression, which regulates intracellular ROS levels, thereby enhancing cell viability and conferring DA resistance to pituitary adenoma (PA) cells. Finally, AR targeting agents were used to inhibit AR signaling, downregulate NRF2 transcription, and sensitize PA cells to BRC treatment. Conclusion and Innovation: We demonstrated that AR plays a crucial role in mediating DA resistance in PRL adenoma. Mechanistically, AR promotes cell proliferation and PRL secretion and confers drug resistance by transcriptionally regulating NRF2 expression to maintain redox homeostasis in PA cells. Finally, combining AR targeting agents with BRC shows promise as a therapeutic strategy for treating PRL adenomas. Antioxid. Redox Signal. 42, 954-972.

Keywords

DA resistance; NRF2; androgen receptor; enzalutamide; prolactin-secreting pituitary adenoma.

Figures
Products