title: Anti-tumor effects of fibroblast growth factor-binding protein (FGF-BP) knockdown in colon carcinoma.
abstract: BACKGROUND
  Fibroblast growth factors FGF-1 and FGF-2 are often upregulated in tumors, but tightly bound to heparan sulphate proteoglycans of the extracellular matrix (ECM). One mechanism of their bioactivation relies on the FGF-binding protein (FGF-BP) which, upon reversible binding to FGF-1 or -2, leads to their release from the ECM. FGF-BP increases tumorigenicity and is highly expressed in tumors like colon carcinoma. In this paper, we analyse cellular and molecular consequences of RNAi-mediated FGF-BP knockdown in colon carcinoma, and explore the therapeutic effects of the nanoparticle-mediated delivery of small interfering RNAs (siRNAs) for FGF-BP targeting.
  
  
  RESULTS
  Employing stable RNAi cells, we establish a dose-dependence of cell proliferation on FGF-BP expression levels. Decreased proliferation is mirrored by alterations in cell cycle distribution and upregulation of p21, which is relevant for mediating FGF-BP effects. While inhibition of proliferation is mainly associated with reduced Akt and increased GSK3β activation, antibody array-based analyses also reveal other alterations in MAPK signalling. Additionally, we demonstrate induction of apoptosis, mediated through caspase-3/7 activation, and alterations in redox status upon FGF-BP knockdown. These effects are based on the upregulation of Bad, Bax and HIF-1α, and the downregulation of catalase. In a therapeutic FGF-BP knockdown approach based on RNAi, we employ polymer-based nanoparticles for the in vivo delivery of siRNAs into established wildtype colon carcinoma xenografts. We show that the systemic treatment of mice leads to the inhibition of tumor growth based on FGF-BP knockdown.
  
  
  CONCLUSIONS
  FGF-BP is integrated in a complex network of cytoprotective effects, and represents a promising therapeutic target for RNAi-based knockdown approaches.
authors: Institute of Pharmacology, Faculty of Medicine, Philipps-University Marburg, Germany.
authors: Daniel
authors: D
authors: Schulze
authors: Philipp
authors: P
authors: Plohmann
authors: Sabrina
authors: S
authors: Höbel
authors: Achim
authors: A
authors: Aigner
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles; D009368:Neoplasm Transplantation; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; C070699:FGFBP1 protein, human