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.
Highlights
Proproteins are synthesized as inactive precursor proteins and require limited proteolysis to be converted into bioactive proteins and peptides
To assess the presence of furin and other proprotein convertase (PC) in pediatric sarcomas we examined the mRNA levels of all nine known PCs in 5 Ewing sarcoma, 8 osteosarcoma and 20 rhabdomyosarcoma (RMS) cell lines
No consistent pattern of expression could be observed between furin and PACE4 in the different cell lines, and no clear difference between alveolar RMS and embryonal RMS cell lines was evident
Summary
Proproteins are synthesized as inactive precursor proteins and require limited proteolysis to be converted into bioactive proteins and peptides. They are usually cleaved at the general consensus motif R/K-Xn-R/K#, where n = 0, 2, 4 or 6 and X rarely Cys or Pro [1]. Seven mammalian proprotein convertases (PCs) cleaving substrates at dibasic motifs have been described: PC1/3, PC2, furin, PC4, PC5, PACE4 and PC7. PCs mediate the tissue-specific endoproteolytic activation of precursor proteins, including hormones, neuropeptides, growth factors and their receptors, adhesion molecules, bacterial toxins and viral glycoproteins. The Proprotein Convertase Furin in RMS Progression
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