Presenilin1 exerts antiproliferative effects by repressing the Wnt/β-catenin pathway in glioblastoma
| Autor: | Mao-jun Liao, Lunshan Xu, Peng-fei Wu, Wei Yang, Liang Yi, Jian-xing Ma, Minhui Xu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Proliferation
lcsh:Medicine Biochemistry S Phase 0302 clinical medicine Cyclin D1 Phosphorylation Wnt Signaling Pathway beta Catenin 0303 health sciences biology Chemistry lcsh:Cytology Brain Neoplasms Wnt signaling pathway Cell cycle Prognosis 030220 oncology & carcinogenesis Down-Regulation Mice Nude Proto-Oncogene Proteins c-myc 03 medical and health sciences Glioma Cell Line Tumor medicine Presenilin-1 Animals Humans lcsh:QH573-671 Molecular Biology neoplasms 030304 developmental biology Cell Proliferation Cell growth lcsh:R Methodology G1 Phase Presenilin1 Cell Biology medicine.disease Xenograft Model Antitumor Assays nervous system diseases Transplantation Catenin Proteolysis biology.protein Cancer research Cyclin-dependent kinase 6 Glioblastoma |
| Zdroj: | Cell Communication and Signaling : CCS Cell Communication and Signaling, Vol 18, Iss 1, Pp 1-13 (2020) |
| ISSN: | 1478-811X |
| Popis: | Background Glioblastoma and Alzheimer’s disease (AD) are the most common and devastating diseases in the central nervous system. The dysfunction of Presenilin1 is the main reason for AD pathogenesis. However, the molecular function of Presenilin1 and its relative mechanism in glioblastoma remain unclear. Methods Expression of presenilin1 in glioma was determined by IHC. CCK-8, colony formation, Flow cytometry, Edu staining were utilized to evaluate functions of presenilin1 on glioblastoma proliferation. The mechanism of above process was assessed by Western blotting and cell immunofluorescence. Mouse transplanting glioblastoma model and micro-MRI detection were used to verified presenilin1 function in vivo. Results In this study, we found that all grades of glioma maintained relatively low Presenilin1 expression and that the expression of Presenilin1 in high-grade glioma was significantly lower than that in low-grade glioma. Moreover, the Presenilin1 level had a positive correlation with glioma and glioblastoma patient prognosis. Next, we determined that Presenilin1 inhibited the growth and proliferation of glioblastoma cells by downregulating CDK6, C-myc and Cyclin D1 to arrest the cell cycle at the G1/S phase. Mechanistically, Presenilin1 promoted the direct phosphorylation of β-catenin at the 45 site and indirect phosphorylation at the 33/37/41 site, then decreased the stabilized part of β-catenin and hindered its translocation from the cytoplasm to the nucleus. Furthermore, we found that Presenilin1 downregulation clearly accelerated the growth of subcutaneous glioblastoma, and Presenilin1 overexpression significantly repressed the subcutaneous and intracranial transplantation of glioblastoma by hindering β-catenin-dependent cell proliferation. Conclusion Our data implicate the antiproliferative effect of Presenilin1 in glioblastoma by suppressing Wnt/β-catenin signaling, which may provide a novel therapeutic agent for glioblastoma. |
| Databáze: | OpenAIRE |
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