title: Human osteosarcoma cells respond to sorafenib chemotherapy by downregulation of the tumor progression factors S100A4, CXCR4 and the oncogene FOS.
abstract: Osteosarcoma is a rare but aggressive bone neoplasm in humans, which is commonly treated with surgery, classical chemotherapy and radiation. Sorafenib, an inhibitor of a number of kinases targeting the Raf/MEK/ERK pathway, is a promising new chemotherapeutic agent in human medicine that has been approved since 2006 for the therapy of renal cell carcinoma and since 2007 for the treatment of hepatocellular carcinoma. Here, we studied the antimetastatic potential of 4 µM of this multikinase inhibitor in a human osteosarcoma cell line. DNA microarray-based gene expression profiling detected 297 and 232 genes upregulated or downregulated at a threshold of >2-fold expression alteration (P<0.05) in the sorafenib-treated cells. Three genes (CXCR4, FOS and S100A4) that are involved in tumor progression were chosen for validation by quantitative PCR (qPCR) and protein expression analysis. The decrease in RNA expression detected by microarray profiling was confirmed by qPCR for all three genes (P<0.01). On the protein level, sorafenib-induced reduction of S100A4 was verified both by western blotting and immunohistochemistry. For CXCR4 and c-Fos, a reduced protein expression was shown by immunohistochemistry, for c-Fos also by immunoblotting. We conclude that sorafenib could serve as a potent chemotherapeutical agent by which to inhibit the metastatic progression of osteosarcomas.
authors.affiliation: Institute of Anatomy, Histology and Embryology, University of Veterinary Medicine, 1210 Vienna, Austria.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Walter
authors.affiliation: Clinic for Companion Animal Medicine, Unit for Internal Medicine, University of Veterinary Medicine, 1210 Vienna, Austria.
authors.forename: Birgitt
authors.initials: B
authors.lastname: Wolfesberger
authors.affiliation: Institute for Medical Biochemistry, University of Veterinary Medicine, 1210 Vienna, Austria.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Miller
authors.affiliation: VetOmics Core Facility, VetCore, University of Veterinary Medicine, 1210 Vienna, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Mair
authors.affiliation: VetOmics Core Facility, VetCore, University of Veterinary Medicine, 1210 Vienna, Austria.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Burger
authors.affiliation: ZMF, Medical University, 8010 Graz, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Gallè
authors.affiliation: VetOmics Core Facility, VetCore, University of Veterinary Medicine, 1210 Vienna, Austria.
authors.forename: Ralf
authors.initials: R
authors.lastname: Steinborn
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D016761:Oncogene Proteins v-fos / Q000235:genetics / Q000378:metabolism*; D012516:Osteosarcoma; D010671:Phenylurea Compounds / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism*; D000077157:Sorafenib; D059467:Transcriptome / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C527276:CXCR4 protein, human; D016761:Oncogene Proteins v-fos; D010671:Phenylurea Compounds; D019718:Receptors, CXCR4; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C077591:S100A4 protein, human; D009536:Niacinamide; D000077157:Sorafenib