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High expression of RAD18 in glioma induces radiotherapy resistance via down-regulating P53 expression
Bing Wu1, Heyuan Wang2, Lenign Zhang3
1NHC Key Lab of Radiobiology, Jilin University, Changchun, Jilin 130021, China; Department of Neurosurgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, China.
Abstract:
As a key regulator of DNA translesion synthesis (TLS) pathway, RAD18 is reported to be abnormally expressed in many kinds of cancers. In glioma, RAD18 was overexpressed in the primary and recurrent glioblastoma multiforme specimens, and its overexpression weakened ionizing radiation-induced apoptosis in glioma A172 cells. Moreover, A172 cells with mutational P53 also showed enhanced radiation resistance. And RAD18 activation induced by cyclin-dependent kinase 2 (CDK2) was repressed by P53. However, whether P53 involves in RAD18-induced radiation resistance remains unknown. Therefore, this study was conducted to explore the effects and mechanism of RAD18 in the radiation resistance of glioma and study P53 role in this process. Results showed that, RAD18 expression was obviously elevated in glioma tissues and cell lines such as U251, SHG-44, A172, U-87 MG and U-118 MG as compared with the normal brain tissues and neuroglia cells. Up-regulation of RAD18 in U-118 MG and A172 cells with lentivirus infection significantly increased cell growth and inhibited cell apoptosis, determined by CCK-8 and flow cytometry technologies. Besides, RAD18 overexpression enhanced cell growth and inhibited cell apoptosis after U-118 MG or A172 cells were irradiated at a dose of 4 Gy. On the contrary, silencing of endogenous RAD18 sensitized U-118 MG and A172 cells to radiation. Moreover, RAD18 and P53 proteins were co-located in the nucleus, and up-regulation of RAD18 decreased the expression of P53 protein and facilitated its nuclear export. Furthermore, cell growth promotion and cell apoptosis inhibition induced by RAD18 up-regulation were impaired when P53 expression was up-regulated under radiation condition. In a word, this study clarifies that RAD18 functions as a promoter in glioma progression and reduces glioma cells' sensibility to radiation through down-regulating P53, which provides new strategies to overcome the radiation resistance in glioma.
Insights
RAD18 promotes glioma progression and radiation resistance by down-regulating P53. Silencing RAD18 or restoring P53 can overcome this resistance, offering new therapeutic strategies for glioma.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- RAD18, a DNA translesion synthesis regulator, is abnormally expressed in cancers.
- RAD18 overexpression is linked to increased radiation resistance in glioma cells.
- The role of P53 in RAD18-mediated radiation resistance in glioma is not fully understood.
Purpose of the Study:
- To investigate the role and mechanism of RAD18 in glioma radiation resistance.
- To elucidate the involvement of P53 in this process.
Main Methods:
- Quantitative analysis of RAD18 expression in glioma tissues and cell lines.
- Lentivirus-mediated gene manipulation (up-regulation and silencing) of RAD18.
- Cell proliferation (CCK-8) and apoptosis (flow cytometry) assays.
- Immunofluorescence to assess protein co-localization and nuclear export.
Main Results:
- RAD18 expression is significantly elevated in glioma tissues and cell lines.
- RAD18 up-regulation enhances glioma cell growth and inhibits apoptosis, increasing radioresistance.
- RAD18 overexpression leads to decreased P53 expression and nuclear export.
- Restoring P53 expression counteracts RAD18-induced radioresistance.
Conclusions:
- RAD18 promotes glioma progression and reduces sensitivity to radiation by down-regulating P53.
- Targeting RAD18 or modulating P53 levels offers potential strategies to overcome glioma radiation resistance.
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