title: The proprotein convertase furin is required to maintain viability of alveolar rhabdomyosarcoma cells.
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.
authors: Department of Oncology and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors: Patricia
authors: P
authors: Jaaks
authors: Department of Oncology and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors: Gianmarco
authors: G
authors: Meier
authors: Department of Oncology and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors: Nagjie
authors: N
authors: Alijaj
authors: Department of Oncology and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors: Eva
authors: E
authors: Brack
authors: Department of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors: Peter
authors: P
authors: Bode
authors: Department of Oncology/Hematology/Immunology, Olgahospital, Klinikum Stuttgart, Stuttgart, Germany.
authors: Ewa
authors: E
authors: Koscielniak
authors: Department of Oncology and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors: Marco
authors: M
authors: Wachtel
authors: Department of Oncology and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors: Beat W
authors: BW
authors: Schäfer
authors: Department of Oncology and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
authors: Michele
authors: M
authors: Bernasconi
mesh_terms: D000818:Animals; D017209:Apoptosis; D001706:Biopsy; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D004195:Disease Models, Animal; D004789:Enzyme Activation; D045683:Furin / Q000235:genetics* / Q000378:metabolism; D020868:Gene Silencing; D064593:Heterografts; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D018232:Rhabdomyosarcoma, Alveolar / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D047368:Tumor Burden
chemical_list: D034741:RNA, Small Interfering; D045683:Furin; D020169:Caspases
keywords: IGF1R; apoptosis; furin; proprotein convertases; rhabdomyosarcoma