RRC ID 51827
Author Jaaks P, D'Alessandro V, Grob N, Büel S, Hajdin K, Schäfer BW, Bernasconi M.
Title The Proprotein Convertase Furin Contributes to Rhabdomyosarcoma Malignancy by Promoting Vascularization, Migration and Invasion.
Journal PLoS One
Abstract The proprotein convertase (PC) furin cleaves precursor proteins, an important step in the activation of many cancer-associated proteins. Substrates of furin and furin-like PCs play a role in proliferation, metastasis and invasion. Some of them are involved in the progression of the pediatric soft tissue sarcoma rhabdomyosarcoma (RMS). In this study, we show that PCs, and in particular furin, are expressed in RMS cell lines. To investigate the functional role of furin, we generated RMS cell lines with modulated furin activity. Silencing or stable inhibition of furin delayed tumor growth in Rh30 and RD xenografts in vivo, and was correlated with lower microvessel density. Reduced furin activity also decreased migration and invasion abilities in vitro, and inhibition of furin in RMS cells diminished processing of IGF1R, VEGF-C, PDGF-B and MT1-MMP, leading to lower levels of mature proteins. Furthermore, we found that furin activity is required for proper IGF signaling in RMS cells, as furin silencing resulted in reduced phosphorylation of Akt upon IGF1 stimulation. Taken together, our results suggest that furin plays an important role in the malignant phenotype of RMS cells by activating proteins involved in tumor growth and vascularization, metastasis and invasion.
Volume 11(8)
Pages e0161396
Published 2016-1-1
DOI 10.1371/journal.pone.0161396
PII PONE-D-16-18721
PMID 27548722
PMC PMC4993484
MeSH Animals Cell Line, Tumor Cell Movement Furin / antagonists & inhibitors Furin / genetics* Furin / metabolism Gene Expression Regulation, Neoplastic* Humans Insulin-Like Growth Factor I / genetics Insulin-Like Growth Factor I / metabolism Matrix Metalloproteinase 14 / genetics Matrix Metalloproteinase 14 / metabolism Mice Mice, Inbred NOD Mice, SCID Neoplasm Invasiveness Neoplasm Transplantation Neovascularization, Pathologic / genetics* Neovascularization, Pathologic / metabolism Neovascularization, Pathologic / pathology Phosphorylation Proto-Oncogene Proteins c-akt / genetics Proto-Oncogene Proteins c-akt / metabolism Proto-Oncogene Proteins c-sis / genetics Proto-Oncogene Proteins c-sis / metabolism RNA, Small Interfering / genetics RNA, Small Interfering / metabolism Receptors, Somatomedin / genetics Receptors, Somatomedin / metabolism Rhabdomyosarcoma / genetics* Rhabdomyosarcoma / metabolism Rhabdomyosarcoma / pathology Signal Transduction Soft Tissue Neoplasms / genetics* Soft Tissue Neoplasms / metabolism Soft Tissue Neoplasms / pathology Transplantation, Heterologous Vascular Endothelial Growth Factor C / genetics Vascular Endothelial Growth Factor C / metabolism Xenograft Model Antitumor Assays
IF 2.74
Times Cited 8
Resource
Human and Animal Cells NRS-1(RCB1188)