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Front. Mol. Neurosci. | doi: 10.3389/fnmol.2018.00092

Endothelial Monocyte-Activating Polypeptide-II Induces BNIP3-mediated Mitophagy to Enhance Temozolomide Cytotoxicity of Glioma Cells via Down-regulating MiR-24-3p

Jian zhang1, 2, Libo Liu3, 4, Yixue Xue3, 4, Yawen Ma1, 2, Xiaobai Liu1, 2, Zhen Li1, 2, Li Zhiqing3, 4 and  Yunhui Liu1, 2*
  • 1Shengjing Hospital of China Medical University, China
  • 2Liaoning Research Center for Translational Medicine in Nervous System Disease, China
  • 3Department of Neurobiology, College of Basic Medicine, China Medical University, China
  • 4Key Laboratory of Cell Biology, Basic Medical College, China Medical University, China

Preliminary studies have shown that endothelial-monocyte-activating polypeptide-II (EMAP-II) and temozolomide (TMZ) alone can exert cytotoxic effects on glioma cells. This study explored whether EMAP-II can enhance the cytotoxic effects of TMZ on glioma stem cells (GSCs) and the possible mechanisms associated with Bcl-2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)-mediated mitophagy facilitated by miR-24-3p regulation. The combination of TMZ and EMAP-II significantly inhibited GSCs viability, migration and invasion, resulting in upregulation of the autophagy biomarker microtubule-associated protein one light chain 3 (LC3)-II/I but down-regulation of the proteins P62, TOMM 20 and CYPD, changes indicative of the occurrence of mitophagy. BNIP3 expression increased significantly in GSCs after treatment with the combination of TMZ and EMAP-II. BNIP3 overexpression strengthened the cytotoxic effects of EMAP-II and TMZ by inducing mitophagy. The combination of EMAP-II and TMZ decreased the expression of miR-24-3p, whose target gene was BNIP3. MiR-24-3p inhibited mitophagy and promoted proliferation, migration and invasion by down-regulating BNIP3 in GSCs. Furthermore, nude mice subjected to miR-24-3p silencing combined with EMAP-II and TMZ treatment displayed the smallest tumours and the longest survival rate. According to the above results, we concluded that EMAP-II enhanced the cytotoxic effects of TMZ on GSCs’ proliferation, migration and invasion both in vitro and in vivo.

Keywords: GSCS, EMAP-II, TMZ, BNIP3, mitophagy

Received: 29 Nov 2017; Accepted: 08 Mar 2018.

Edited by:

Andrei Surguchov, University of Kansas Medical Center, United States

Reviewed by:

Paul B. Fisher, Virginia Commonwealth University, United States
Ralf S. Schmid, Department of Medicine, University of Pennsylvania, United States  

Copyright: © 2018 zhang, Liu, Xue, Ma, Liu, Li, Zhiqing and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Yunhui Liu, Shengjing Hospital of China Medical University, Shenyang, China,