COX-2/sEH dual inhibitor PTUPB suppresses glioblastoma growth by targeting epidermal growth factor receptor and hyaluronan mediated motility receptor.

Junyang Li,Xiangjun Ji,Handong Wang,Yongyue Gao,Liwen Li,Yali Zhou,Sung Hee Hwang,Bruce D Hammock

doi:10.18632/oncotarget.20928

Abstract

AimsCyclooxygenase-2 (COX-2)/soluble epoxide hydrolase (sEH) dual inhibitor, PTUPB, has been demonstrated to inhibit angiogenesis, primary tumor growth and metastasis. The aim of this study is to investigate the effects of PTUPB on glioblastoma cells and xenograft model.ResultsWe show here that PTUPB inhibits glioblastoma cell proliferation and G1 phase cell cycle arrest in vitro, and suppresses the tumor growth and angiogenesis in vivo. The expression and activation of epidermal growth factor receptor (EGFR) and its downstream kinases, ERK1/2 and AKT, are reduced by PTUPB, indicating that the EGF/EGFR signaling pathway is a potential target. Moreover, PTUPB dramatically suppresses expression of hyaluronan mediated motility receptor (HMMR) in the glioblastoma cell lines and xenograft mouse model, suggesting that the HMMR is the other potential target.Materials and MethodsCellular immunofluorescence assays were used for cell staining of actin fibers and HMMR. CCK-8 kit was used for cell proliferation assay. Cell-cycle analysis was performed by flow cytometry. Quantitative real-time PCR assay was performed to test mRNA level. Western blot analysis was used to test protein expression. Immunohistochemical staining assay was used for xenograft tumor tissue staining of Ki-67, CD31 and HMMR. The SPSS version 17.0 software was applied for statistical analysis.ConclusionsOur data demonstrate that PTUPB is a potential therapeutic agent to treat glioblastomas.

Highlights

Glioblastomas are the most malignant central nervous system (CNS) tumors in adults
Our data demonstrate that PTUPB is a potential therapeutic agent to treat glioblastomas
We demonstrated that PTUPB inhibits cell proliferation and G1 phase cell cycle arrest in glioblastoma cell lines, and suppresses both tumorigenesis and angiogenesis in glioblastoma xenografts

Summary

Introduction

Glioblastomas are the most malignant central nervous system (CNS) tumors in adults. Despite the recent advances in therapeutic strategies including surgery, radiotherapy and chemotherapy, the prognosis of glioblastoma patients remains poor with a median survival of less than one year [1,2,3]. Glioblastomas are highly vascularized and lead to rapid cell proliferation [4]. Therapies of anti-angiogenesis and anti-tumorigenesis should be concurrently considered for glioblastoma treatment. An earlier study demonstrated that bevacizumab plus radiotherapy and temozolomide do not improve survival in glioblastoma patients [1], a recent exploratory analysis suggested that the addition of bevacizumab to standard glioblastoma treatment may extend survival for patients who do not receive second-line therapy [5]. The cyclooxygenase-2 (COX-2) signaling pathway in the arachidonic acid (ARA)

Methods

Results

Conclusion