1. Dopamine receptor D2 regulates glioblastoma survival and death through MET and death receptor 4/5
- Author
-
Hye-Min Jeon, Young Taek Oh, Yong Jae Shin, Nakho Chang, Donggeun Kim, Donghun Woo, Yoon Yeup, Kyeung Min Joo, Heejin Jo, Heekyoung Yang, Jin-Ku Lee, Wonyoung Kang, Jason Sa, Won Jun Lee, James Hale, Justin D. Lathia, Benjamin Purow, Myung Jin Park, Jong Bae Park, Do-Hyun Nam, and Jeongwu Lee
- Subjects
Dopamine receptor ,Glioblastoma ,GBM stem cells ,MET ,TRAIL receptor ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
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.
- Published
- 2023
- Full Text
- View/download PDF