Related Experiment Video
Updated: Aug 5, 2025
Human Neural Organoids for Studying Brain Cancer and Neurodegenerative Diseases
Published on: June 28, 2019
Dopamine receptor D2 regulates glioblastoma survival and death through MET and death receptor 4/5
Hye-Min Jeon1, Young Taek Oh2, Yong Jae Shin3
1Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
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.
Insights
Dopamine receptor D2 (DRD2) signaling drives glioblastoma growth by activating MET, but inhibiting DRD2 triggers cell death via TRAIL receptors. This reveals a key molecular pathway for glioblastoma survival and death.
Area of Science:
- Neuro-oncology
- Molecular oncology
- Cancer signaling pathways
Background:
- Dopamine receptor signaling, traditionally linked to the central nervous system, is increasingly recognized for its role in cancer.
- Dopamine receptor D2 (DRD2) is a therapeutic target in glioblastoma (GBM), with clinical trials investigating DRD2 inhibitors like ONC201.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying DRD2 signaling in glioblastoma.
- To identify proteins interacting with DRD2 in GBM.
- To understand how DRD2 signaling influences GBM stem-like cells and tumor growth.
Main Methods:
- Utilized human GBM patient-derived tumors treated with dopamine receptor agonists and antagonists.
- Identified proteins interacting with DRD2.
- Investigated the downstream signaling pathways activated by DRD2, including MET and TRAIL receptors.
Main Results:
- DRD2 signaling promotes glioblastoma stem-like cells and tumor growth through MET activation.
- Pharmacological inhibition of DRD2 leads to DRD2-TRAIL receptor interaction and subsequent cancer cell death.
- Demonstrated a molecular circuitry where MET and TRAIL receptors mediate GBM survival and death, respectively, governed by DRD2 signaling.
Conclusions:
- DRD2 signaling plays a dual role in glioblastoma, promoting growth via MET and enabling cell death induction via TRAIL receptors upon inhibition.
- Tumor-derived dopamine and dopamine biosynthesis enzyme expression in GBM may serve as biomarkers for patient stratification in DRD2-targeted therapies.
More Related Videos
Related Concept Videos
01:28Drugs Affecting GI Tract Motility: Dopamine Receptor Antagonists
01:30Overview of Cell Death
Cell death was observed in the early 19th century, but there was no experimental evidence to prove it. In 1842, Carl Vogt first discovered cell death in a metamorphic toad; however, it was not termed ‘cell death.’ Scientists discovered different cell death pathways only in the...
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...
01:22PI3K/mTOR/AKT Signaling Pathway
01:15Receptor Downregulation in MVBs
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR...
02:38Mitogens and the Cell Cycle