Regulation of p53wt glioma cell proliferation by androgen receptor-mediated inhibition of small VCP/p97-interacting protein expression.

Dejun Bao,Rong Xing,Chaoshi Niu,Junyan Sun,Yang Wang,Bo Zhang,Shengyun Fang,Hua Zhao,Chuandong Cheng,Xiaoqiang Lan,Zhuo Chen

doi:10.18632/oncotarget.15509

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.

Highlights

We found that androgen receptor (AR) expressed in the glioma cell lines, neuroblastoma cells, and neurons but not www.impactjournals.com/oncotarget in glial cells
We demonstrated the effect of R1881 treatment on increased AR protein level and decreased protein and mRNA level of small VCP/p97-interacting protein (SVIP) in both U87 and U251 cells, respectively
To investigate SVIP’s impact on cell proliferation, MTT, soft agar assay as well as cell number count were performed in p53 wildtype cells, U87, and HeLa, as well as U251 and SKBR3 p53 mutant cells

Summary

Introduction

Gliomas constitute approximately 30% of all brain and central nervous system tumors and 80% of all malignant brain tumors and are rarely curable [1]. According to a report in 2008, out of 10000 Americans diagnosed each year with malignant gliomas, approximately half were alive one year after diagnosis, and 25% after two years [2], whereas glioblastoma multiform (GBM) has a worse prognosis [3]. The exact causes of gliomas are still unclear. An epidemiological survey has demonstrated that the incidence of glioma in men is about 1.5 to 2 fold of that in women, regardless of etiologies [4, 5], suggesting a sex-related discrepancy. With respect to the differences in sex hormones between the two genders, the androgen/

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Conclusion