التفاصيل البيبلوغرافية
| العنوان: |
The dopamine receptor D1 inhibitor, SKF83566, suppresses GBM stemness and invasion through the DRD1-c-Myc-UHRF1 interactions |
| المؤلفون: |
Xue, Zhiyi, Zhang, Yan, Zhao, Ruiqi, Liu, Xiaofei, Grützmann, Konrad, Klink, Barbara, Zhang, Xun, Wang, Shuai, Zhao, Wenbo, Sun, Yanfei, Han, Mingzhi, Wang, Xu, Hu, Yaotian, Liu, Xuemeng, Yang, Ning, Qiu, Chen, Li, Wenjie, Huang, Bin, Li, Xingang, Bjerkvig, Rolf, Wang, Jian, Zhou, Wenjing |
| المساهمون: |
University of Bergen |
| المصدر: |
Journal of Experimental & Clinical Cancer Research ; volume 43, issue 1 ; ISSN 1756-9966 |
| بيانات النشر: |
Springer Science and Business Media LLC |
| سنة النشر: |
2024 |
| مصطلحات موضوعية: |
Cancer Research, Oncology |
| الوصف: |
Background Extensive local invasion of glioblastoma (GBM) cells within the central nervous system (CNS) is one factor that severely limits current treatments. The aim of this study was to uncover genes involved in the invasion process, which could also serve as therapeutic targets. For the isolation of invasive GBM cells from non-invasive cells, we used a three-dimensional organotypic co-culture system where glioma stem cell (GSC) spheres were confronted with brain organoids (BOs). Using ultra-low input RNA sequencing (ui-RNA Seq), an invasive gene signature was obtained that was exploited in a therapeutic context. Methods GFP-labeled tumor cells were sorted from invasive and non-invasive regions within co-cultures. Ui-RNA sequencing analysis was performed to find a gene cluster up-regulated in the invasive compartment. This gene cluster was further analyzed using the Connectivity MAP (CMap) database. This led to the identification of SKF83566, an antagonist of the D1 dopamine receptor (DRD1), as a candidate therapeutic molecule. Knockdown and overexpression experiments were performed to find molecular pathways responsible for the therapeutic effects of SKF83566. Finally, the effects of SKF83566 were validated in orthotopic xenograft models in vivo. Results Ui-RNA seq analysis of three GSC cell models (P3, BG5 and BG7) yielded a set of 27 differentially expressed genes between invasive and non-invasive cells. Using CMap analysis, SKF83566 was identified as a selective inhibitor targeting both DRD1 and DRD5. In vitro studies demonstrated that SKF83566 inhibited tumor cell proliferation, GSC sphere formation, and invasion. RNA sequencing analysis of SKF83566-treated P3, BG5, BG7, and control cell populations yielded a total of 32 differentially expressed genes, that were predicted to be regulated by c-Myc. Of these, the UHRF1 gene emerged as the most downregulated gene following treatment, and ChIP experiments revealed that c-Myc binds to its promoter region. Finally, SKF83566, or stable DRD1 knockdown, ... |
| نوع الوثيقة: |
article in journal/newspaper |
| اللغة: |
English |
| DOI: |
10.1186/s13046-024-02947-7 |
| DOI: |
10.1186/s13046-024-02947-7.pdf |
| DOI: |
10.1186/s13046-024-02947-7/fulltext.html |
| الإتاحة: |
https://doi.org/10.1186/s13046-024-02947-7Test |
| حقوق: |
https://creativecommons.org/licenses/by/4.0Test ; https://creativecommons.org/licenses/by/4.0Test |
| رقم الانضمام: |
edsbas.2BCACD85 |
| قاعدة البيانات: |
BASE |
