Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Tumor Biology
Published in: Tumor Biology 12/2016

01-12-2016 | Original Article

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

Authors: Shaofeng Yan, Hao Xue, Ping Zhang, Xiao Han, Xing Guo, Guang Yuan, Lin Deng, Gang Li

Published in: Tumor Biology | Issue 12/2016

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
Shen J, Li G, Liu Q, He Q, Gu J, et al. Marchantin C: a potential anti-invasion agent in glioma cells. Cancer Biol Ther. 2010;9:33–9.CrossRefPubMed
2.
Yan S, Han X, Xue H, Zhang P, Guo X, et al. Let-7f inhibits glioma cell proliferation, migration, and invasion by targeting Periostin. J Cell Biochem. 2015;116:1680–92.CrossRefPubMed
3.
Zhai GG, Malhotra R, Delaney M, Latham D, Nestler U, et al. Radiation enhances the invasive potential of primary glioblastoma cells via activation of the rho signaling pathway. J Neuro-Oncol. 2006;76:227–37.CrossRef
4.
Deng L, Li G, Li R, Liu Q, He Q, et al. Rho-kinase inhibitor, fasudil, suppresses glioblastoma cell line progression in vitro and in vivo. Cancer Biol Ther. 2010;9:875–84.CrossRefPubMed
5.
Wang M, Yoshida D, Liu S, Teramoto A. Inhibition of cell invasion by indomethacin on glioma cell lines: in vitro study. J Neuro-Oncol. 2005;72:1–9.CrossRef
6.
Carragher NO, Walker SM, Scott Carragher LA, Harris F, Sawyer TK, et al. Calpain 2 and Src dependence distinguishes mesenchymal and amoeboid modes of tumour cell invasion: a link to integrin function. Oncogene. 2006;25:5726–40.CrossRefPubMed
7.
Steward WP, Thomas AL. Marimastat: the clinical development of a matrix metalloproteinase inhibitor. Expert Opin Investig Drugs. 2000;9:2913–22.CrossRefPubMed
8.
Gadea G, Sanz-Moreno V, Self A, Godi A, Marshall CJ. DOCK10-mediated Cdc42 activation is necessary for amoeboid invasion of melanoma cells. Curr Biol. 2008;18:1456–65.CrossRefPubMed
9.
Fujita M, Otsuka Y, Yamada S, Iwakawa M, Imai T. X-ray irradiation and rho-kinase inhibitor additively induce invasiveness of the cells of the pancreatic cancer line, MIAPaCa-2, which exhibits mesenchymal and amoeboid motility. Cancer Sci. 2011;102:792–8.CrossRefPubMed
10.
Friedl P, Wolf K. Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer. 2003;3:362–74.CrossRefPubMed
11.
Paulus W, Baur I, Beutler AS, Reeves SA. Diffuse brain invasion of glioma cells requires beta 1 integrins. Lab Investig. 1996;75:819–26.PubMed
12.
Lin J, Teo S, Lam DH, Jeyaseelan K, Wang S. MicroRNA-10b pleiotropically regulates invasion, angiogenicity and apoptosis of tumor cells resembling mesenchymal subtype of glioblastoma multiforme. Cell Death Dis. 2012;3:e398.CrossRefPubMedPubMedCentral
13.
Gadea G, de Toledo M, Anguille C, Roux P. Loss of p53 promotes RhoA-ROCK-dependent cell migration and invasion in 3D matrices. J Cell Biol. 2007;178:23–30.CrossRefPubMedPubMedCentral
14.
Sahai E, Marshall CJ. Differing modes of tumour cell invasion have distinct requirements for rho/ROCK signalling and extracellular proteolysis. Nat Cell Biol. 2003;5:711–9.CrossRefPubMed
15.
16.
Song Y, Wang P, Zhao W, Yao Y, Liu X, et al. MiR-18a regulates the proliferation, migration and invasion of human glioblastoma cell by targeting neogenin. Exp Cell Res. 2014;324:54–64.CrossRefPubMed
17.
Torka R, Thuma F, Herzog V, Kirfel G. ROCK signaling mediates the adoption of different modes of migration and invasion in human mammary epithelial tumor cells. Exp Cell Res. 2006;312:3857–71.CrossRefPubMed
18.
Kakiashvili E, Dan Q, Vandermeer M, Zhang Y, Waheed F, et al. The epidermal growth factor receptor mediates tumor necrosis factor-alpha-induced activation of the ERK/GEF-H1/RhoA pathway in tubular epithelium. J Biol Chem. 2011;286:9268–79.CrossRefPubMedPubMedCentral
19.
Mishima T, Naotsuka M, Horita Y, Sato M, Ohashi K, et al. LIM-kinase is critical for the mesenchymal-to-amoeboid cell morphological transition in 3D matrices. Biochem Biophys Res Commun. 2010;392:577–81.CrossRefPubMed
20.
Zhang J, Sarkar S, Yong VW. The chemokine stromal cell derived factor-1 (CXCL12) promotes glioma invasiveness through MT2-matrix metalloproteinase. Carcinogenesis. 2005;26:2069–77.CrossRefPubMed
21.
Peng J, He F, Zhang C, Deng X, Yin F. Protein kinase C-alpha signals P115RhoGEF phosphorylation and RhoA activation in TNF-alpha-induced mouse brain microvascular endothelial cell barrier dysfunction. J Neuroinflammation. 2011;8:28.CrossRefPubMedPubMedCentral
22.
Noha M, Yoshida D, Watanabe K, Teramoto A. Suppression of cell invasion on human malignant glioma cell lines by a novel matrix-metalloproteinase inhibitor SI-27: in vitro study. J Neuro-Oncol. 2000;48:217–23.CrossRef
23.
Oppel F, Muller N, Schackert G, Hendruschk S, Martin D, et al. SOX2-RNAi attenuates S-phase entry and induces RhoA-dependent switch to protease-independent amoeboid migration in human glioma cells. Mol Cancer. 2011;10:137.CrossRefPubMedPubMedCentral
24.
Taddei ML, Giannoni E, Morandi A, Ippolito L, Ramazzotti M, et al. Mesenchymal to amoeboid transition is associated with stem-like features of melanoma cells. Cell Commun Signal. 2014;12:24.CrossRefPubMedPubMedCentral
25.
Zhao P, Zhang W, Wang SJ, Yu XL, Tang J, et al. HAb18G/CD147 promotes cell motility by regulating annexin II-activated RhoA and Rac1 signaling pathways in hepatocellular carcinoma cells. Hepatology. 2011;54:2012–24.CrossRefPubMed
26.
Eitaki M, Yamamori T, Meike S, Yasui H, Inanami O. Vincristine enhances amoeboid-like motility via GEF-H1/RhoA/ROCK/myosin light chain signaling in MKN45 cells. BMC Cancer. 2012;12:469.CrossRefPubMedPubMedCentral
27.
Margheri F, Luciani C, Taddei ML, Giannoni E, Laurenzana A, et al. The receptor for urokinase-plasminogen activator (uPAR) controls plasticity of cancer cell movement in mesenchymal and amoeboid migration style. Oncotarget. 2014;5:1538–53.CrossRefPubMedPubMedCentral
28.
Lee J, Moon HJ, Lee JM, Joo CK. Smad3 regulates rho signaling via NET1 in the transforming growth factor-beta-induced epithelial-mesenchymal transition of human retinal pigment epithelial cells. J Biol Chem. 2010;285:26618–27.CrossRefPubMedPubMedCentral
29.
Birukova AA, Birukov KG, Smurova K, Adyshev D, Kaibuchi K, et al. Novel role of microtubules in thrombin-induced endothelial barrier dysfunction. FASEB J. 2004;18:1879–90.CrossRefPubMed
Metadata
Title
MMP inhibitor Ilomastat induced amoeboid-like motility via activation of the Rho signaling pathway in glioblastoma cells
Authors
Shaofeng Yan
Hao Xue
Ping Zhang
Xiao Han
Xing Guo
Guang Yuan
Lin Deng
Gang Li
Publication date
01-12-2016
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 12/2016
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-016-5464-5

Other articles of this Issue 12/2016

Tumor Biology 12/2016 Go to the issue

Review

Diverse roles of miR-335 in development and progression of cancers

Original Article

RETRACTED ARTICLE: MiR-429 regulates gastric cancer cell invasiveness through ZEB proteins

Original Article

MiRNA-221-3p desensitizes pancreatic cancer cells to 5-fluorouracil by targeting RB1

Original Article

miR-122 inhibits cancer cell malignancy by targeting PKM2 in gallbladder carcinoma

Original Article

Tissue transglutaminase 2 exerts a tumor-promoting role in hepatitis B virus-related hepatocellular carcinoma

Original Article

MicroRNA-638 inhibits cell proliferation by targeting suppress PIM1 expression in human osteosarcoma
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits