Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Department of System Cancer Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Republic of Korea.
Neoplasia. 2023 May;39:100894. doi: 10.1016/j.neo.2023.100894. Epub 2023 Mar 25.
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.
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。多巴胺受体信号与各种癌症有关，包括神经胶质瘤（GBM），并且是一个公认的治疗靶点，最近的临床试验证明了这一点，这些试验使用了一种选择性多巴胺受体 D2（DRD2）抑制剂 ONC201。了解多巴胺受体信号的分子机制对于开发有效的治疗方法至关重要。使用经过多巴胺受体激动剂和拮抗剂处理的人 GBM 患者来源的肿瘤，我们鉴定出与 DRD2 相互作用的蛋白质。DRD2 信号通过激活 MET 促进神经胶质瘤（GBM）干细胞样细胞和 GBM 生长。相比之下，DRD2 的药理学抑制诱导 DRD2-TRAIL 受体相互作用和随后的细胞死亡。因此，我们的研究结果表明，致癌性 DRD2 信号的分子电路中，MET 和 TRAIL 受体分别是肿瘤细胞存活和细胞死亡的关键因素，分别控制 GBM 的存活和死亡。最后，肿瘤衍生的多巴胺和一组 GBM 中多巴胺生物合成酶的表达可能指导 DRD2 靶向治疗的患者分层。
