Jianhua Cheng , Weiyan Xie , Yiyuan Chen , Yingxuan Sun , Lei Gong , Hongyun Wang , Chuzhong Li , Yazhuo Zhang
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In addition, single-cell sequencing analysis was performed on 3 cases of DA-resistant prolactinomas and 3 cases of sensitive prolactinomas. Furthermore, to screen for potential therapeutic drugs, the study successfully established an </span>organoids<span> model for DA-resistant prolactinomas and screened 180 small molecule compounds using 8 organoids. The efficacy of the identified drugs was verified through various assays, including CCK-8, colony formation, CTG, and flow cytometry, and their mechanisms of action were confirmed through WB and IHC. The effectiveness of the identified drugs was evaluated both in vitro and in vivo.</span></p></div><div><h3>Results</h3><p>The results of transcriptome sequencing and single-cell sequencing analyses showed that DA resistance in prolactinomas is associated with the upregulation of the Focal Adhesion<span><span><span> (FA) signaling pathway. Additionally, immunohistochemical validation revealed that FAK and </span>Paxillin were significantly upregulated in DA-resistant prolactinomas. Screening of 180 small molecule compounds using 8 organoids identified </span>Genistein<span><span> as a potentially effective drug for DA-resistant prolactinomas. Experimental validation demonstrated that Genistein inhibited the proliferation of pituitary tumor cell lines and organoids and promoted </span>apoptosis in pituitary tumor cells. Moreover, both the cell sequencing results and WB validation results of the drug-treated cells indicated that Genistein exerts its anti-tumor effect by inhibiting the FA pathway. In vivo, experiments also showed that Genistein can inhibit subcutaneous tumor formation.</span></span></p></div><div><h3>Conclusion</h3><p>DA resistance in prolactinomas is associated with upregulation of the Focal Adhesion (FA) signaling pathway, and Genistein can exert its anti-tumor effect by inhibiting the expression of the FA pathway.</p></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":null,"pages":null},"PeriodicalIF":15.8000,"publicationDate":"2024-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Drug resistance mechanisms in dopamine agonist-resistant prolactin pituitary neuroendocrine tumors and exploration for new drugs\",\"authors\":\"Jianhua Cheng , Weiyan Xie , Yiyuan Chen , Yingxuan Sun , Lei Gong , Hongyun Wang , Chuzhong Li , Yazhuo Zhang\",\"doi\":\"10.1016/j.drup.2024.101056\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><p>The treatment<span><span> of dopamine agonists<span> (DA) resistant prolactinomas remains a formidable challenge, as the mechanism of resistance is still unclear, and there are currently no viable alternative drug therapies available. This study seeks to investigate the mechanism of DA resistance in prolactinomas and identify new potentially effective </span></span>drugs.</span></p></div><div><h3>Methods</h3><p><span>To explore the mechanism of DA resistance in prolactinomas, this study conducted transcriptome sequencing analysis on 27 cases of DA-resistant prolactinomas and 10 cases of sensitive prolactinomas. In addition, single-cell sequencing analysis was performed on 3 cases of DA-resistant prolactinomas and 3 cases of sensitive prolactinomas. Furthermore, to screen for potential therapeutic drugs, the study successfully established an </span>organoids<span> model for DA-resistant prolactinomas and screened 180 small molecule compounds using 8 organoids. The efficacy of the identified drugs was verified through various assays, including CCK-8, colony formation, CTG, and flow cytometry, and their mechanisms of action were confirmed through WB and IHC. The effectiveness of the identified drugs was evaluated both in vitro and in vivo.</span></p></div><div><h3>Results</h3><p>The results of transcriptome sequencing and single-cell sequencing analyses showed that DA resistance in prolactinomas is associated with the upregulation of the Focal Adhesion<span><span><span> (FA) signaling pathway. Additionally, immunohistochemical validation revealed that FAK and </span>Paxillin were significantly upregulated in DA-resistant prolactinomas. Screening of 180 small molecule compounds using 8 organoids identified </span>Genistein<span><span> as a potentially effective drug for DA-resistant prolactinomas. Experimental validation demonstrated that Genistein inhibited the proliferation of pituitary tumor cell lines and organoids and promoted </span>apoptosis in pituitary tumor cells. 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引用次数: 0
摘要
背景多巴胺受体激动剂（DA）耐药的泌乳素瘤的治疗仍然是一项艰巨的挑战，因为其耐药机制尚不清楚，而且目前还没有可行的替代药物疗法。为了探索泌乳素瘤的DA耐药机制，本研究对27例DA耐药的泌乳素瘤和10例敏感的泌乳素瘤进行了转录组测序分析。此外，还对3例DA耐药泌乳素瘤和3例敏感泌乳素瘤进行了单细胞测序分析。此外，为了筛选潜在的治疗药物，该研究成功建立了耐DA催乳素瘤的器官组织模型，并利用8个器官组织筛选了180种小分子化合物。通过CCK-8、菌落形成、CTG和流式细胞术等多种检测方法验证了所发现药物的疗效，并通过WB和IHC证实了这些药物的作用机制。结果转录组测序和单细胞测序分析结果显示，催乳素瘤的DA耐药性与病灶粘附（FA）信号通路的上调有关。此外，免疫组化验证显示，FAK 和 Paxillin 在 DA 抗性催乳素瘤中显著上调。利用 8 个器官组织对 180 种小分子化合物进行了筛选，发现 Genistein 是治疗 DA 抗性催乳素瘤的潜在有效药物。实验验证表明，Genistein 能抑制垂体瘤细胞系和器官组织的增殖，并促进垂体瘤细胞的凋亡。此外，药物处理细胞的细胞测序结果和 WB 验证结果均表明，染料木素是通过抑制 FA 通路来发挥抗肿瘤作用的。结论催乳素瘤的抗药性与Focal Adhesion（FA）信号通路的上调有关，而Genistein可以通过抑制FA通路的表达来发挥抗肿瘤作用。
Drug resistance mechanisms in dopamine agonist-resistant prolactin pituitary neuroendocrine tumors and exploration for new drugs
Background
The treatment of dopamine agonists (DA) resistant prolactinomas remains a formidable challenge, as the mechanism of resistance is still unclear, and there are currently no viable alternative drug therapies available. This study seeks to investigate the mechanism of DA resistance in prolactinomas and identify new potentially effective drugs.
Methods
To explore the mechanism of DA resistance in prolactinomas, this study conducted transcriptome sequencing analysis on 27 cases of DA-resistant prolactinomas and 10 cases of sensitive prolactinomas. In addition, single-cell sequencing analysis was performed on 3 cases of DA-resistant prolactinomas and 3 cases of sensitive prolactinomas. Furthermore, to screen for potential therapeutic drugs, the study successfully established an organoids model for DA-resistant prolactinomas and screened 180 small molecule compounds using 8 organoids. The efficacy of the identified drugs was verified through various assays, including CCK-8, colony formation, CTG, and flow cytometry, and their mechanisms of action were confirmed through WB and IHC. The effectiveness of the identified drugs was evaluated both in vitro and in vivo.
Results
The results of transcriptome sequencing and single-cell sequencing analyses showed that DA resistance in prolactinomas is associated with the upregulation of the Focal Adhesion (FA) signaling pathway. Additionally, immunohistochemical validation revealed that FAK and Paxillin were significantly upregulated in DA-resistant prolactinomas. Screening of 180 small molecule compounds using 8 organoids identified Genistein as a potentially effective drug for DA-resistant prolactinomas. Experimental validation demonstrated that Genistein inhibited the proliferation of pituitary tumor cell lines and organoids and promoted apoptosis in pituitary tumor cells. Moreover, both the cell sequencing results and WB validation results of the drug-treated cells indicated that Genistein exerts its anti-tumor effect by inhibiting the FA pathway. In vivo, experiments also showed that Genistein can inhibit subcutaneous tumor formation.
Conclusion
DA resistance in prolactinomas is associated with upregulation of the Focal Adhesion (FA) signaling pathway, and Genistein can exert its anti-tumor effect by inhibiting the expression of the FA pathway.
期刊介绍：
Drug Resistance Updates serves as a platform for publishing original research, commentary, and expert reviews on significant advancements in drug resistance related to infectious diseases and cancer. It encompasses diverse disciplines such as molecular biology, biochemistry, cell biology, pharmacology, microbiology, preclinical therapeutics, oncology, and clinical medicine. The journal addresses both basic research and clinical aspects of drug resistance, providing insights into novel drugs and strategies to overcome resistance. Original research articles are welcomed, and review articles are authored by leaders in the field by invitation.
Articles are written by leaders in the field, in response to an invitation from the Editors, and are peer-reviewed prior to publication. Articles are clear, readable, and up-to-date, suitable for a multidisciplinary readership and include schematic diagrams and other illustrations conveying the major points of the article. The goal is to highlight recent areas of growth and put them in perspective.
*Expert reviews in clinical and basic drug resistance research in oncology and infectious disease
*Describes emerging technologies and therapies, particularly those that overcome drug resistance
*Emphasises common themes in microbial and cancer research
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