title: Blocking signaling at the level of GLI regulates downstream gene expression and inhibits proliferation of canine osteosarcoma cells.
abstract: The Hedgehog-GLI signaling pathway is active in a variety of human malignancies and is known to contribute to the growth and survival of human osteosarcoma cells. In this study, we examined the expression and regulation of GLI transcription factors in multiple canine osteosarcoma cell lines and analyzed the effects of inhibiting GLI with GANT61, a GLI-specific inhibitor. Compared with normal canine osteoblasts, real-time PCR showed that GLI1 and GLI2 were highly expressed in two out of three cell lines and correlated with downstream target gene expression of PTCH1and PAX6. Treatment of canine osteosarcoma cells with GANT61 resulted in decreased expression of GLI1, GLI2, PTCH1, and PAX6. Furthermore, GANT61 inhibited proliferation and colony formation in all three canine osteosarcoma cell lines. The finding that GLI signaling activity is present and active in canine osteosarcoma cells suggests that spontaneously arising osteosarcoma in dogs might serve as a good model for future preclinical testing of GLI inhibitors.
authors.affiliation: The Department of Surgical and Radiological Sciences, University of California Davis School of Veterinary Medicine, Davis, California, United States of America.
authors.forename: Mehdi Hayat
authors.initials: MH
authors.lastname: Shahi
authors.affiliation: The Department of Surgical and Radiological Sciences, University of California Davis School of Veterinary Medicine, Davis, California, United States of America.
authors.forename: Roseline
authors.initials: R
authors.lastname: Holt
authors.affiliation: The Department of Surgical and Radiological Sciences, University of California Davis School of Veterinary Medicine, Davis, California, United States of America.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Rebhun
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D053823:Hedgehog Proteins / Q000378:metabolism; D012516:Osteosarcoma / Q000473:pathology*; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C551027:GANT 61; D053823:Hedgehog Proteins; D011725:Pyridines; D011743:Pyrimidines; D014157:Transcription Factors