Abstract
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Success of current therapies is still limited and outcome is particularly poor for metastatic alveolar rhabdomyosarcoma (aRMS). We previously identified the proprotein convertase furin as potential target for specific drug delivery with RMS-homing peptides. Furin is a protease that converts inactive precursor proteins into bioactive proteins and peptides. In this study, we investigate the biological role of furin in aRMS progression in vitro and in vivo. Furin expression was confirmed in over 86% RMS biopsies in a tissue microarray (n=89). Inducible furin silencing in vitro led to significant impairment of cell viability and proliferation in all investigated aRMS cell lines, but not in MRC5 fibroblasts. Furthermore, the aRMS cell lines Rh3 and Rh4 revealed to be very sensitive to furin silencing, undergoing caspase-dependent cell death. Notably, furin silencing in vivo led to complete remission of established Rh4 tumors and to delayed growth in Rh30 tumors. Taken together, these findings identify furin as an important factor for aRMS progression and survival. Thus, we propose furin as a novel therapeutic target for treatment of aRMS.
Highlights
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma, representing 5-8% of all childhood cancers
Decrease of furin led to clear reduction of mature IGF1Rβ, indicating that furin activity is lowered upon silencing of furin (Figure 1C). mRNA levels of other proprotein convertases (PCs), examined by qRTPCR after 48h of treatment with 25 ng/mL DOX, were unaffected suggesting that furin silencing was specific and was not compensated for by increased mRNA expression of other PCs (Supplementary Figure S1B)
Furin silencing had no effect on MRC5 fibroblast viability, suggesting that alveolar rhabdomyosarcoma (aRMS), but not normal cells are dependent on furin activity
Summary
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma, representing 5-8% of all childhood cancers. ARMS is more aggressive and is associated with a poorer prognosis with a 5-year survival of 48% [1]. Around 80% of aRMS tumors harbor the chimeric transcription factor PAX3/7-FOXO1 inducing a specific gene expression signature [2, 3]. A dominant role of PAX3/7-FOXO1 as oncogenic driver has been suggested [4, 5]. Despite the dependence of aRMS tumors on PAX3/7-FOXO1 expression, transcription factors in general represent a challenging target. Many efforts have been made to characterize key pathways driving RMS progression in order to identify targets for novel therapeutic approaches. The insulin-like growth factor 1 receptor (IGF1R) is one among them. IGF1R is a transcriptional target of PAX3-FOXO1 [6]
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