title: Inhibition of Notch pathway prevents osteosarcoma growth by cell cycle regulation.
abstract: The study shows constitutive activation of the Notch pathway in various types of malignancies. However, it remains unclear how the Notch pathway is involved in the pathogenesis of osteosarcoma. We investigated the expression of the Notch pathway molecules in osteosarcoma biopsy specimens and examined the effect of Notch pathway inhibition. Real-time PCR revealed overexpression of Notch2, Jagged1, HEY1, and HEY2. On the other hand, Notch1 and DLL1 were downregulated in biopsy specimens. Notch pathway inhibition using gamma-secretase inhibitor and CBF1 siRNA slowed the growth of osteosarcomas in vitro. In addition, gamma-secretase inhibitor-treated xenograft models exhibited significantly slower osteosarcoma growth. Cell cycle analysis revealed that gamma-secretase inhibitor promoted G1 arrest. Real-time PCR and western blot revealed that gamma-secretase inhibitor reduced the expression of accelerators of the cell cycle, including cyclin D1, cyclin E1, E2, and SKP2. On the other hand, p21(cip1) protein, a cell cycle suppressor, was upregulated by gamma-secretase inhibitor treatment. These findings suggest that inhibition of Notch pathway suppresses osteosarcoma growth by regulation of cell cycle regulator expression and that the inactivation of the Notch pathway may be a useful approach to the treatment of patients with osteosarcoma.
authors.affiliation: Department of Orthopaedic Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tanaka
authors.forename: T
authors.initials: T
authors.lastname: Setoguchi
authors.forename: M
authors.initials: M
authors.lastname: Hirotsu
authors.forename: H
authors.initials: H
authors.lastname: Gao
authors.forename: H
authors.initials: H
authors.lastname: Sasaki
authors.forename: Y
authors.initials: Y
authors.lastname: Matsunoshita
authors.forename: S
authors.initials: S
authors.lastname: Komiya
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D001842:Bone and Bones / Q000378:metabolism; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007124:Immunoenzyme Techniques; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D018797:Cell Cycle Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497570:RBPJ protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases