Inhibition of Intermedin (Adrenomedullin 2) Suppresses the Growth of Glioblastoma and Increases the Antitumor Activity of Temozolomide

Luping Huang,Lingmiao Kong,Haili Zhang,Heng Zhang,Denian Wang,Huan Zhao,Hongyu Li,Wei Zhang,Yong'Gang Wei,Fei Xiao,Min Li,Fei Liu,Zhongxue Feng

doi:10.1158/1535-7163.mct-20-0619

Abstract

Glioblastoma multiforme (GBM; grade IV glioma) is the most malignant type of primary brain tumor and is characterized by rapid proliferation and invasive growth. Intermedin (IMD) is an endogenous peptide belonging to the calcitonin gene-related peptide family and has been reported to play an important role in cell survival and invasiveness in several types of cancers. In this study, we found that the expression level of IMD was positively related to the malignancy grade of gliomas. The highest expression of IMD was found in GBM, indicating that IMD may play an important role in glioma malignancy. IMD increased the invasive ability of glioma cells by promoting filopodia formation, which is dependent on ERK1/2 activation. IMD-induced ERK1/2 phosphorylation also promoted GBM cell proliferation. In addition, IMD enhanced mitochondrial function and hypoxia-induced responses in GBM cells. Treatment with anti-IMD monoclonal antibodies not only inhibited tumor growth in both ectopic and orthotopic models of GBM but also significantly enhanced the antitumor activity of temozolomide. Our study may provide novel insights into the mechanism of GBM cell invasion and proliferation and provide an effective strategy to improve the therapeutic effect of GBM treatments.

Highlights

Glioma is the most common tumor in the central nervous system [1,2,3,4]
IMD increased the invasive ability of glioma cells by promoting filopodia formation, which is dependent on ERK1/2 activation
The Western blot (WB) analysis showed that the expression of IMD in high-grade gliomas, the glioblastoma multiforme (GBM), were significantly higher than that in low-grade gliomas (Supplementary Fig. S2)

Summary

Introduction

Glioma is the most common tumor in the central nervous system [1,2,3,4]. Grades I and II gliomas are low-grade gliomas, which are relatively histologically benign and have a good prognosis, there is still a chance of recurrence or increased malignancy. High-grade gliomas account for more than two-thirds of all intracranial primary malignancies [1, 4]. Grade IV glioma, called glioblastoma multiforme (GBM), is the most malignant type of primary brain tumor and is characterized by rapid cell proliferation, invasive growth to surrounding tissues, abundant neovascularization, and repeated recurrence [1,2,3,4]. The main treatments for GBM are surgery, Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Methods

Results

Conclusion