Abstract 3571: Furin activity: A driver of rhabdomyosarcoma progression

Abstract

Abstract Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. The prognosis and survival rate is often very poor and therefore new therapy approaches are required. Thus, we focus on 1) employing RMS-specific peptides for targeted delivery of chemotherapeutics to the tumor site and 2) identifying novel therapeutic targets. In a previous study we discovered that RMS-homing peptides bind preferably to the proprotein convertase furin. Initial investigations confirmed a high expression of furin throughout different pediatric soft tissue sarcoma types and hinted that furin promotes the tumorigenic phenotype of RMS cells in vitro as well as in corresponding xenografts in vivo. Here we present a novel approach of tetracycline-induced shRNA-based silencing of furin in vitro and in vivo in order to investigate in depth the role of furin in RMS progression. Furin depletion was confirmed at mRNA, protein and activity level and led to impaired maturation furin substrates insulin like growth factor 1 receptor (IGF1R) and transforming growth factor beta 1 (TGFβ-1). We found that loss of furin activity suppresses the malignant phenotype of Rh30 cells by decreasing proliferation and affecting formation of colonies. Furthermore, we observed increased caspase 3/7 activity and enrichment of nucleosomes in the cytoplasm upon furin depletion, thus hinting initiation of apoptotic processes. Induction of furin silencing in RMS xenografts in NOD/SCID mice delayed tumour growth, indicating a crucial role of furin in early phases of tumour growth. Taken together, our data underscore the importance of furin for RMS progression and therefore targeting the activity of furin represents a promising tool for treatment of RMS. Citation Format: Patricia AIM Jaaks, Gianmarco Meier, Beat W. Schäfer, Michele Bernasconi. Furin activity: A driver of rhabdomyosarcoma progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3571. doi:10.1158/1538-7445.AM2015-3571