RIOK2 Inhibitor NSC139021 Exerts Anti-Tumor Effects on Glioblastoma via Inducing Skp2-Mediated Cell Cycle Arrest and Apoptosis.

Min Yu,Junlei Chang,Fei Lu,Jingyu Yan,Ying Wang,Xiaoyan Hu

doi:10.3390/biomedicines9091244

Abstract

Up to now, the chemotherapy approaches for glioblastoma were limited. 1-[2-Thiazolylazo]-2-naphthol (named as NSC139021) was shown to significantly inhibit the proliferation of prostate cancer cells by targeting the atypical protein kinase RIOK2. It is documented that RIOK2 overexpressed in glioblastoma. However, whether NSC139021 can inhibit the growth of glioblastoma cells and be a potential drug for glioblastoma treatment need to be clarified. In this study, we investigated the effects of NSC139021 on human U118MG, LN-18, and mouse GL261 glioblastoma cells and the mouse models of glioblastoma. We verified that NSC139021 effectively inhibited glioblastoma cells proliferation, but it is independent of RIOK2. Our data showed that NSC139021 induced cell cycle arrest at G0/G1 phase via the Skp2-p27/p21-Cyclin E/CDK2-pRb signaling pathway in G1/S checkpoint regulation. In addition, NSC139021 also increased the apoptosis of glioblastoma cells by activating the p53 signaling pathway and increasing the levels of Bax and cleaved caspase 3. Furthermore, intraperitoneal administration of 150 mg/kg NSC139021 significantly suppressed the growth of human and mouse glioblastoma in vivo. Our study suggests that NSC139021 may be a potential chemotherapy drug for the treatment of glioblastoma by targeting the Skp2-p27/p21-Cyclin E/CDK2-pRb signaling pathway.

Highlights

Glioblastoma (GBM) is one of the most common and aggressive primary malignant neoplasms of the central nervous system with a high mortality rate [1,2]
The phosphorylation level of G1/S checkpoint Rb decreased by NSC139021 in U118MG and LN-18 cells (Figure 3E,F). These results indicated that the effect of NSC139021 blocked cell cycle in G0/G1 phase was time- and dose-dependent manner through regulating the Skp2-p27/p21-CDK2-Rb axis of G1/S
These results indicated that NSC139021 triggered apoptosis in glioblastoma cells, and this was associated with p53-caspase3 activation

Summary

Introduction

Glioblastoma (GBM) is one of the most common and aggressive primary malignant neoplasms of the central nervous system with a high mortality rate [1,2]. The current standard treatment includes surgical resection, followed by a combination of radiation and chemotherapy with temozolomide (TMZ) [3,4]. Despite extensive efforts to develop new treatment strategies, the median survival for patients with GBM is 15 to 20 months from the time of diagnosis, and only 3% to 5% of patients survive longer than 5 years [5]. TMZ as a DNA alkylating agent targeting proliferating cells only exhibited modest efficacy, which in combination with radiation can only increase the survival time by about 3 months compared to radiotherapy alone [6,7,8] and improve the 2-year survival rate from 10% to. New chemotherapy drugs for GBM are urgently needed

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Results

Conclusion