Kang Yang1, Minghai Wei1, Zhaofei Yang2,3, Zhenfa Fu2,3, Ruixue Xu4, Cheng Cheng2,3, Xi Chen2,3, Sheng Chen5, Eric Dammer6, Weidong Le7,8,9. 1. Dalian Medical University, Dalian, People's Republic of China. 2. Liaoning Provincial Center for Clinical Research on Neurological Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China. 3. Liaoning Provincial Key Laboratory for Research on Pathogenic Mechanisms of Neurological Diseases,, The First Affiliated Hospital of Dalian Medical University, Dalian, People's Republic of China. 4. Department of Neurosurgery, The First Affiliated Hospital of Dalian Medical University, Dalian, People's Republic of China. 5. Department of Neurology, The Ruijin Hospital of Shanghai Jiao-Tong University School of Medicine, Shanghai, China. 6. Emory School of Medicine and Center for Neurodegenerative Disease, Atlanta, GA, USA. 7. Liaoning Provincial Center for Clinical Research on Neurological Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China. wdle@sibs.ac.cn. 8. Liaoning Provincial Key Laboratory for Research on Pathogenic Mechanisms of Neurological Diseases,, The First Affiliated Hospital of Dalian Medical University, Dalian, People's Republic of China. wdle@sibs.ac.cn. 9. 1st Hospital of Dalian Medical University, 193 Lianhe Street, Liaoning Province, Dalian, People's Republic of China. wdle@sibs.ac.cn.
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.
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.
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