Gu Weiting, Zhang Weifeng, Wu Zhebao, Cai Yu
Department of Neurosurgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
J Neurooncol. 2025 May;172(3):587-597. doi: 10.1007/s11060-025-04949-7. Epub 2025 Feb 1.
To investigate the molecular mechanisms underlying resistance to dopamine agonists (DA).
LC-MS/MS analysis was performed on rat pituitary neuroendocrine tumors (PitNET) cell line GH3 to identify differentially expressed proteins induced by cabergoline (CAB) treatment. A total of 180 human PITNET samples were subjected to transcriptome analysis. Immunohistochemistry (IHC) was conducted on 29 tumor samples to validate NDFIP1 alteration. A xenograft mouse model was established by subcutaneously injecting GH3 cells, with or without NDFIP1 overexpression, into nude mice to investigate tumor growth. PitNET cell lines were treated with CAB. Cell proliferation was assessed using the CCK-8, and protein expression levels were examined through Western blot analysis.
CAB treatment upregulated FDFT1 and NDFIP1 protein expression in GH3 cells, with NDFIP1 showing a significant positive correlation with tumor size, as confirmed by IHC results. MMQ and GH3 cells overexpressing NDFIP1 exhibited enhanced viability and reduced sensitivity to CAB. In vivo experiments demonstrated that subcutaneous injection of NDFIP1-overexpressing GH3 cells led to enhanced tumor growth compared to parental GH3 cells. Although the total levels of PTEN remained unaltered, NDFIP1 overexpression induced PTEN nuclear translocation, potentially activating the mTOR pathway. This was supported by increased phosphorylation of key mTOR pathway components, including p-AKT and p-4EBP1, in cells overexpressing NDFIP1.
CAB treatment induces the upregulation of NDFIP1 in PitNET cells, which correlates with tumor size and contributes to reduced CAB sensitivity, potentially through activation of the mTOR pathway. NDFIP1 as a potential therapeutic target for overcoming DA resistance in PitNET patients.
研究对多巴胺激动剂（DA）耐药的分子机制。
对大鼠垂体神经内分泌肿瘤（PitNET）细胞系GH3进行液相色谱-串联质谱（LC-MS/MS）分析，以鉴定卡麦角林（CAB）处理诱导的差异表达蛋白。对总共180个人类PitNET样本进行转录组分析。对29个肿瘤样本进行免疫组织化学（IHC）以验证NDFIP1改变。通过将过表达或未过表达NDFIP1的GH3细胞皮下注射到裸鼠中建立异种移植小鼠模型，以研究肿瘤生长。用CAB处理PitNET细胞系。使用CCK-8评估细胞增殖，并通过蛋白质印迹分析检测蛋白质表达水平。
CAB处理上调了GH3细胞中FDFT1和NDFIP1蛋白表达，IHC结果证实NDFIP1与肿瘤大小呈显著正相关。过表达NDFIP1的MMQ和GH3细胞表现出活力增强和对CAB的敏感性降低。体内实验表明，与亲代GH3细胞相比，皮下注射过表达NDFIP1的GH3细胞导致肿瘤生长增强。尽管PTEN的总水平保持不变，但NDFIP1过表达诱导PTEN核转位，可能激活mTOR途径。这得到了过表达NDFIP1的细胞中关键mTOR途径成分（包括p-AKT和p-4EBP1）磷酸化增加的支持。
CAB处理诱导PitNET细胞中NDFIP1上调，这与肿瘤大小相关，并可能通过激活mTOR途径导致CAB敏感性降低。NDFIP1作为克服PitNET患者DA耐药性的潜在治疗靶点。
