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Activation of dopamine receptor D1 inhibits glioblastoma tumorigenicity by regulating autophagic activity

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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.

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Data availability

All data generated or analyzed during this study are included in this article, and are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank Professor Zixu Mao from Emory University for his critical reading and revision advice.

Funding

This work was supported by grants from the National Natural Science Foundation of China (NSFC) [number 81430021 and 81771521], and a Liaoning provincial key research project grant [number 2018225051].

Author information

Authors and Affiliations

  1. Dalian Medical University, Dalian, People’s Republic of China

    Kang Yang & Minghai Wei

  2. Liaoning Provincial Center for Clinical Research on Neurological Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian, People’s Republic of China

    Zhaofei Yang, Zhenfa Fu, Cheng Cheng, Xi Chen & Weidong Le

  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

    Zhaofei Yang, Zhenfa Fu, Cheng Cheng, Xi Chen & Weidong Le

  4. Department of Neurosurgery, The First Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China

    Ruixue Xu

  5. Department of Neurology, The Ruijin Hospital of Shanghai Jiao-Tong University School of Medicine, Shanghai, China

    Sheng Chen

  6. Emory School of Medicine and Center for Neurodegenerative Disease, Atlanta, GA, USA

    Eric Dammer

  7. 1st Hospital of Dalian Medical University, 193 Lianhe Street, Liaoning Province, Dalian, People’s Republic of China

    Weidong Le

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  1. Kang Yang
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Contributions

Study conception and design were performed by Kang Yang and Weidong Le. Material preparation, data collection and analysis were performed by Kang Yang, Zhaofei Yang, Zhenfa Fu, Minghai Wei, Ruixue Xu and Sheng Chen. The first draft of the manuscript was written by Kang Yang. The manuscript was reviewed and revised by Cheng Cheng, Xi Chen, Feng zhang and Eric Dammer. All authors commented on previous versions of the manuscript, and read and approved the final manuscript.

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Correspondence to Weidong Le.

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Ethics approval and consent to participate

The study was approved by the Ethics Committee of the second hospital of DMU and followed the ethical guidelines of Declaration of Helsinki. Written informed consent was obtained from all patients whose tissues were used in this study. Mice were purchased from the Institute of Genome-Engineered Animal Models of Dalian Medical University (DMU) and were kept under specific pathogen-free (SPF) conditions. The study protocol was approved by the Animal Ethics Committee of DMU.

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Yang, K., Wei, M., Yang, Z. et al. Activation of dopamine receptor D1 inhibits glioblastoma tumorigenicity by regulating autophagic activity. Cell Oncol. 43, 1175–1190 (2020). https://doi.org/10.1007/s13402-020-00550-4

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