1. Activation of dopamine receptor D1 inhibits glioblastoma tumorigenicity by regulating autophagic activity.
- Author
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Yang K, Wei M, Yang Z, Fu Z, Xu R, Cheng C, Chen X, Chen S, Dammer E, and Le W
- Subjects
- Animals, Calcium metabolism, Carcinogenesis drug effects, Carcinogenesis pathology, Cell Line, Tumor, Cell Proliferation drug effects, Glioblastoma metabolism, Glioblastoma ultrastructure, Humans, Intracellular Space metabolism, Lysosomes drug effects, Lysosomes metabolism, MAP Kinase Signaling System drug effects, Mice, Inbred BALB C, Mice, Nude, Models, Biological, Receptors, Dopamine D1 antagonists & inhibitors, TOR Serine-Threonine Kinases metabolism, Temozolomide pharmacology, Treatment Outcome, Xenograft Model Antitumor Assays, Autophagy drug effects, Carcinogenesis metabolism, Glioblastoma pathology, Receptors, Dopamine D1 metabolism
- Abstract
Purpose: Recent studies have reported important roles of dopamine receptors in the early development and progression of glioblastoma (GBM). Here, we tested the antitumor activity of a Dopamine receptor D1 (DRD1) agonist, either alone or in combination with temozolomide (TMZ) on GBM cells., Methods: Immunofluorescence, immunohistochemistry and Western blotting were used to detect dopamine receptor expression in primary human GBM tissues. In addition, clinical data of GBM patients downloaded from The Cancer Genome Atlas (TCGA) were analyzed. Image-based tracking analysis of LC3 using a mCherry-eGFP-LC3 plasmid was utilized to monitor autophagic flux. Transmission electron microscopy (TEM) was used to visualize aggregation of autophagosomes/autolysosomes. Finally, DRD1 agonist (SKF83959)-induced inhibition of GBM growth was assessed in vitro and in vivo., Results: Positive DRD1 expression was observed in human GBM tissues and found to be related with a good clinical outcome. DRD1 activation specifically inhibited GBM cell growth and significantly disrupted autophagic flux, which led to tumor cell death. Moreover, we found that DRD1 agonist treatment inhibited auto-lysosomal degradation in GBM cells and that this process was calcium overload dependent and related to inhibition of mammalian target of rapamycin (mTOR). Finally, we found that DRD1 agonist and TMZ co-treatment yielded a synergistic therapeutic effect both in vivo and in vitro., Conclusions: From our data we conclude that DRD1 activation inhibits GBM cell growth and may serve as an alternative avenue for the design of future GBM therapies.
- Published
- 2020
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