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Tumor Biology

, Volume 37, Issue 12, pp 16177–16186 | Cite as

MMP inhibitor Ilomastat induced amoeboid-like motility via activation of the Rho signaling pathway in glioblastoma cells

  • Shaofeng Yan
  • Hao Xue
  • Ping Zhang
  • Xiao Han
  • Xing Guo
  • Guang Yuan
  • Lin Deng
  • Gang Li
Original Article
  • 272 Downloads

Abstract

Matrix metalloproteinases (MMPs) play the important role in the process of glioblastoma cell invasion through 3D matrices. However, the effects of MMP inhibitors used in the treatment of malignant gliomas are unsatisfactory. The aim of this study was to explore the reason and mechanism by which cells move through the dense extracellular matrix without proteolysis. The results showed that MMP inhibitor (MMPI), Ilomastat, induced glioma cells to have an amoeboid-like morphology with invasive ability. Moreover, the RhoA/Rho kinase (ROCK)/myosin light chain (MLC) signal is involved in the MMPI-induced movement mode switch, and RhoA activation is dependent on P115RhoGEF. Importantly, combined inhibition of MMPs and ROCK enhanced the inhibition invasion function of MMPI and increased survival time in vitro and in vivo. The results suggested that glioma cells with MMPI treatment were able to compensate for the loss of invasive proteolysis-dependent migration capacity by acquiring an amoeboid-like migration mode and indicated that the combined MMP inhibitor and ROCK inhibitor can be used as an attractive antitumor drug candidate for the treatment of GBM.

Keywords

Matrix metalloproteinases Ilomastat Glioblastoma Amoeboid Mesenchymal 

Abbreviations

AMT

Amoeboid–mesenchymal transition

GBM

Glioblastoma

ILO

Ilomastat

MAT

Mesenchymal–amoeboid transition

MMPs

Matrix metalloproteinases

MMPI

Matrix metalloproteinase inhibitor

ROCKI ROCK

Inhibitor

Notes

Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (nos. 81101594, 81372719, 81172403). We thank Professor Xun Qu for her helpful comments and advice to this work and thank Dr. Edward C. Mignot, Shandong University, for linguistic advice.

Compliance with ethical standards

Conflicts of interest

None

Supplementary material

13277_2016_5464_MOESM1_ESM.tif (8.4 mb)
Fig. S1 The effect on apoptotic or necrotic cell death when T98G and U251 cells were treated with ILO Hoechst33342 test shows no apoptotic or necrotic cell death was detected in response to ILO at 50 μM in the both glioma cell lines (TIFF 8589 kb)
13277_2016_5464_Fig1_ESM.gif (70 kb)

High resolution image (GIF 70 kb)

13277_2016_5464_MOESM2_ESM.tif (680 kb)
Fig. S2 The effect on the cell viability when T98G and U251 cells were treated with Y-27,632 CCK8 test shows Y-27,632 at a concentration of 10 μM did not affect the cell viability in the both glioma cell lines (TIFF 679 kb)
13277_2016_5464_Fig2_ESM.gif (14 kb)

High resolution image (GIF 14 kb)

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  1. 1.Department of Neurosurgery, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
  2. 2.Department of NeurosurgeryQilu Hospital of Shandong UniversityJinan,China
  3. 3.Department of NeurosurgeryZibo Zhong Xin HospitalZiboChina

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