PMID- 32761562 OWN - NLM STAT- MEDLINE DCOM- 20210805 LR - 20211204 IS - 2211-3436 (Electronic) IS - 2211-3428 (Linking) VI - 43 IP - 6 DP - 2020 Dec TI - Activation of dopamine receptor D1 inhibits glioblastoma tumorigenicity by regulating autophagic activity. PG - 1175-1190 LID - 10.1007/s13402-020-00550-4 [doi] AB - 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. FAU - Yang, Kang AU - Yang K AD - Dalian Medical University, Dalian, People's Republic of China. FAU - Wei, Minghai AU - Wei M AD - Dalian Medical University, Dalian, People's Republic of China. FAU - Yang, Zhaofei AU - Yang Z AD - Liaoning Provincial Center for Clinical Research on Neurological Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China. AD - 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. FAU - Fu, Zhenfa AU - Fu Z AD - Liaoning Provincial Center for Clinical Research on Neurological Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China. AD - 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. FAU - Xu, Ruixue AU - Xu R AD - Department of Neurosurgery, The First Affiliated Hospital of Dalian Medical University, Dalian, People's Republic of China. FAU - Cheng, Cheng AU - Cheng C AD - Liaoning Provincial Center for Clinical Research on Neurological Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China. AD - 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. FAU - Chen, Xi AU - Chen X AD - Liaoning Provincial Center for Clinical Research on Neurological Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian, People's Republic of China. AD - 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. FAU - Chen, Sheng AU - Chen S AD - Department of Neurology, The Ruijin Hospital of Shanghai Jiao-Tong University School of Medicine, Shanghai, China. FAU - Dammer, Eric AU - Dammer E AD - Emory School of Medicine and Center for Neurodegenerative Disease, Atlanta, GA, USA. FAU - Le, Weidong AU - Le W AD - 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. AD - 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. AD - 1st Hospital of Dalian Medical University, 193 Lianhe Street, Liaoning Province, Dalian, People's Republic of China. wdle@sibs.ac.cn. LA - eng GR - 81430021/National Natural Science Foundation of China/ GR - 81771521/National Natural Science Foundation of China/ GR - 2018225051/Liaoning provincial key research project/ PT - Journal Article DEP - 20200806 PL - Netherlands TA - Cell Oncol (Dordr) JT - Cellular oncology (Dordrecht) JID - 101552938 RN - 0 (Receptors, Dopamine D1) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - SY7Q814VUP (Calcium) RN - YF1K15M17Y (Temozolomide) SB - IM MH - Animals MH - *Autophagy/drug effects MH - Calcium/metabolism MH - Carcinogenesis/drug effects/*metabolism/pathology MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - Glioblastoma/metabolism/*pathology/ultrastructure MH - Humans MH - Intracellular Space/metabolism MH - Lysosomes/drug effects/metabolism MH - MAP Kinase Signaling System/drug effects MH - Mice, Inbred BALB C MH - Mice, Nude MH - Models, Biological MH - Receptors, Dopamine D1/antagonists & inhibitors/*metabolism MH - TOR Serine-Threonine Kinases/metabolism MH - Temozolomide/pharmacology MH - Treatment Outcome MH - Xenograft Model Antitumor Assays OTO - NOTNLM OT - Autophagy OT - Dopamine agonist OT - Dopamine receptor OT - Glioblastoma OT - Temozolomide EDAT- 2020/08/08 06:00 MHDA- 2021/08/06 06:00 CRDT- 2020/08/08 06:00 PHST- 2019/11/20 00:00 [received] PHST- 2020/07/14 00:00 [accepted] PHST- 2020/07/11 00:00 [revised] PHST- 2020/08/08 06:00 [pubmed] PHST- 2021/08/06 06:00 [medline] PHST- 2020/08/08 06:00 [entrez] AID - 10.1007/s13402-020-00550-4 [pii] AID - 10.1007/s13402-020-00550-4 [doi] PST - ppublish SO - Cell Oncol (Dordr). 2020 Dec;43(6):1175-1190. doi: 10.1007/s13402-020-00550-4. Epub 2020 Aug 6.