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

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.