Dopamine receptor D2 regulates glioblastoma survival and death through MET and death receptor 4/5.
Dopamine receptor D2 regulates glioblastoma survival and death through MET and death receptor 4/5.
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DOI：
10.1016/j.neo.2023.100894
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发表时间：
2023-03
期刊：
影响因子：
4.8
通讯作者：
Hye-Min Jeon;Young-Taek Oh;Y. Shin;Nakho Chang;Donggeun Kim;Donghun Woo;Yoon Yeup;K. Joo;H. Jo;Heekyoung Yang;Jin-Ku Lee;Wonyoung Kang;J. Sa;Won Jun Lee;J. Hale;J. Lathia;B. Purow;Myung-Jin Park;J. B. Park;D. Nam;Jeongwu Lee
中科院分区：
文献类型：
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作者：
Hye-Min Jeon;Young-Taek Oh;Y. Shin;Nakho Chang;Donggeun Kim;Donghun Woo;Yoon Yeup;K. Joo;H. Jo;Heekyoung Yang;Jin-Ku Lee;Wonyoung Kang;J. Sa;Won Jun Lee;J. Hale;J. Lathia;B. Purow;Myung-Jin Park;J. B. Park;D. Nam;Jeongwu Lee
最近的研究表明，传统上与中枢神经系统功能相关的信号分子在癌症中起着关键作用。多巴胺受体信号传导与包括胶质母细胞瘤（GBM）在内的各种癌症有关，并且它是公认的治疗靶点，如最近使用选择性多巴胺受体D2（DRD 2）抑制剂ONC 201的临床试验所证明的。了解多巴胺受体信号传导的分子机制对于开发有效的治疗方案至关重要。使用多巴胺受体激动剂和拮抗剂治疗的人GBM患者来源的肿瘤，我们鉴定了与DRD 2相互作用的蛋白质。DRD 2信号通过激活MET促进胶质母细胞瘤（GBM）干细胞样细胞和GBM生长。相反，DRD 2的药理学抑制诱导DRD 2-TRAIL受体相互作用和随后的细胞死亡。因此，我们的研究结果证明了致癌DRD 2信号传导的分子回路，其中MET和TRAIL受体，肿瘤细胞存活和细胞死亡的关键因素，分别控制GBM存活和死亡。最后，肿瘤衍生的多巴胺和多巴胺生物合成酶在GBM亚组中的表达可以指导DRD 2靶向治疗的患者分层。
Recent studies indicate that signaling molecules traditionally associated with central nervous system function play critical roles in cancer. Dopamine receptor signaling is implicated in various cancers including glioblastoma (GBM) and it is a recognized therapeutic target, as evidenced by recent clinical trials with a selective dopamine receptor D2 (DRD2) inhibitor ONC201. Understanding the molecular mechanism(s) of the dopamine receptor signaling will be critical for development of potent therapeutic options. Using the human GBM patient-derived tumors treated with dopamine receptor agonists and antagonists, we identified the proteins that interact with DRD2. DRD2 signaling promotes glioblastoma (GBM) stem-like cells and GBM growth by activating MET. In contrast, pharmacological inhibition of DRD2 induces DRD2-TRAIL receptor interaction and subsequent cell death. Thus, our findings demonstrate a molecular circuitry of oncogenic DRD2 signaling in which MET and TRAIL receptors, critical factors for tumor cell survival and cell death, respectively, govern GBM survival and death. Finally, tumor-derived dopamine and expression of dopamine biosynthesis enzymes in a subset of GBM may guide patient stratification for DRD2 targeting therapy.