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Regulation of p53wt glioma cell proliferation by androgen receptor-mediated inhibition of small VCP/p97-interacting
Dejun Bao1,2,3, Chuandong Cheng1,2,3, Xiaoqiang Lan4,5
1Department of Neurosurgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, China.
Abstract:
The incidence of glioma in men is higher than that in women; however, little is known about the expression and basic function of the androgen receptor (AR) in gliomas. AR inhibited the small VCP/p97-interacting protein (SVIP) on the transcriptional level was previously reported. The present study shows that the protein level of AR is highly expressed in cell lines of the nervous system. Moreover, the AR expression is increased while SVIP expression is decreased in tumor tissue of glioma patients, which is in agreement with the progressing WHO grades. A statistically significant increase in serum testosterone level of glioma patients compared with that of non-cancer patients was also detected. Furthermore, it has been proved that SVIP is down-regulated as well as AR is up-regulated in glioma cell lines with R1881 treatment. Interestingly, the depletion of SVIP using siRNA facilitated cell proliferation and decreased p53 expression. In addition, overexpression of SVIP increased cell death only in p53wt cell lines. Moreover, U87MG cells, p53wt cell line was susceptible to AR antagonists in vitro and in vivo. The current study provides insight into the biological role of AR in suppressing SVIP and p53 and promoting the progression of glioma as well as the clinical treatment of glioma patients.
Insights
Androgen receptor (AR) expression increases, while SVIP expression decreases in glioma, promoting tumor progression. AR antagonists show potential for treating glioma by targeting AR and SVIP pathways.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Endocrinology
Background:
- Glioma incidence is higher in men, yet the role of androgen receptor (AR) in gliomas is poorly understood.
- Previous research indicated AR inhibits small VCP/p97-interacting protein (SVIP) transcriptionally.
- AR is notably expressed in nervous system cell lines.
Purpose of the Study:
- To investigate the expression and function of androgen receptor (AR) in glioma.
- To explore the relationship between AR, SVIP, and p53 in glioma progression.
- To evaluate the potential of AR antagonists in glioma treatment.
Main Methods:
- Analysis of AR and SVIP protein levels in glioma cell lines and patient tumor tissues.
- Measurement of serum testosterone levels in glioma patients.
- In vitro and in vivo experiments using R1881 treatment, siRNA, and AR antagonists.
- Assessment of cell proliferation, cell death, and p53 expression.
Main Results:
- AR expression increased, and SVIP expression decreased in glioma tissues, correlating with WHO grade.
- Glioma patients showed significantly higher serum testosterone levels.
- R1881 treatment upregulated AR and downregulated SVIP in glioma cells.
- SVIP depletion enhanced cell proliferation and reduced p53 expression.
- SVIP overexpression increased cell death in p53 wild-type cell lines.
- U87MG (p53wt) cells were sensitive to AR antagonists.
Conclusions:
- AR plays a role in suppressing SVIP and p53, thereby promoting glioma progression.
- The AR/SVIP pathway is a potential therapeutic target for glioma.
- AR antagonists demonstrate promise for clinical treatment of glioma.