Xu Linpeng, Lei Zhuowei, Wang Quanji, Jiang Qian, Xing Biao, Li Xingbo, Guo Xiang, Wang Zihan, Li Sihan, Huang Yimin, Lei Ting
Sino-German Neuro-Oncology Molecular Laboratory, Department of Neurosurgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.
Hubei Key Laboratory of Neural Injury and Functional Reconstruction, Huazhong University of Science and Technology, Wuhan, China.
Antioxid Redox Signal. 2025 Jun;42(16-18):954-972. doi: 10.1089/ars.2024.0611. Epub 2024 Nov 6.
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. 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 and . 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. 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. 42, 954-972.
多巴胺激动剂（DAs）是分泌催乳素的垂体腺瘤（PRL腺瘤）患者的一线治疗药物。然而，一部分患者反应不佳，即所谓的DA抵抗。先前的研究报道，DA抵抗在男性患者中更为普遍。本研究旨在探讨雄激素受体（AR）表达与DA抵抗之间的关系，并探索AR介导DA抵抗的潜在机制。我们的结果表明，在我们的DA抵抗性PRL腺瘤队列中，AR表达较高的患者对DA的抵抗性更强。此外，发现AR在体内和体外均参与细胞增殖、PRL分泌以及对溴隐亭（BRC）的抵抗。从机制上讲，我们证明细胞内活性氧（ROS）在BRC治疗后作为凋亡和铁死亡的上游介质发挥作用。作为一种配体依赖性转录因子，AR可转运至细胞核并转录促进NFE2样bZIP转录因子2（NRF2）的表达，NRF2调节细胞内ROS水平，从而增强细胞活力并赋予垂体腺瘤（PA）细胞DA抵抗性。最后，使用AR靶向剂抑制AR信号传导，下调NRF2转录，并使PA细胞对BRC治疗敏感。我们证明AR在介导PRL腺瘤的DA抵抗中起关键作用。从机制上讲，AR通过转录调节NRF2表达来促进细胞增殖和PRL分泌，并赋予耐药性，以维持PA细胞中的氧化还原稳态。最后，将AR靶向剂与BRC联合使用显示出有望成为治疗PRL腺瘤的一种治疗策略。42, 954 - 972。
