title: Preventing MEK1 activation influences the responses of human osteosarcoma cells to bone morphogenetic proteins 2 and 9.
abstract: It was recently suggested that bone morphogenetic protein (BMP)-2 may be useful for treating osteosarcoma cells. BMP-9, which has been patented to treat breast and prostate cancers, has a higher osteoinductive potential than BMP-2. Peptides derived from the knuckle epitope of BMPs (pBMPs) also induced osteogenic differentiation. However, the effect of BMP-9 and pBMPs on osteosarcoma cells is unclear. We analyzed the effects of BMP-2, BMP-9, pBMP-2, and pBMP-9 on the behavior of human MG-63 and SaOS-2 osteosarcoma cells. An inhibitor of MEK1 activation (PD98059) that prevents downstream extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and a specific inhibitor of p38 were also used as mitogen activated protein kinase-targeting therapy is being investigated as a treatment modality for osteosarcoma. BMP-2 and BMP-9 (1.92 nmol/l) induced the phosphorylation of Smad1/5/8 in both osteosarcoma cells within 1 h but had different effects on mitogen activated protein kinase pathways. Whereas BMP-2 mainly activated ERK1/2, BMP-9 phosphorylated p38 within 1 h. pBMP-2 did not activate either the Smad or ERK/p38, whereas pBMP-9, like BMP-9, induced both Smad1/5/8 and p38 phosphorylation. p38 activation by BMP-9 or pBMP-9 was also enhanced by PD98059. However, BMP-2 or BMP-9 increased the amounts of distal-less homeobox 5 and Osterix mRNAs in SaOS-2 cells within 6 h, whereas pBMP-9 had no effect. PD98059 promoted the highest level of Osterix mRNA in SaOS-2 cells incubated with BMP-2 or BMP-9, whereas p38 inhibitor had no effect. Furthermore, PD98059 induced the lowest proliferation of MG-63 cells incubated with BMP-2, whereas p38 inhibitor did not affect the proliferation of either osteosarcoma cell line. Therefore a combination of BMP-2 or BMP-9 and an inhibitor of MEK1 may be a promising tool for regulating osteosarcoma cell behavior.
authors.affiliation: Department of Chemical Engineering and Biotechnological Engineering, Laboratory of Cell-Biomaterial Biohybrid Systems, University of Sherbrooke, Sherbrooke, Québec, J1K 2R1, Canada.
authors.forename: Hyunjin
authors.initials: H
authors.lastname: Park
authors.forename: Olivier
authors.initials: O
authors.lastname: Drevelle
authors.forename: Alex
authors.initials: A
authors.lastname: Daviau
authors.forename: Helena
authors.initials: H
authors.lastname: Senta
authors.forename: Eric
authors.initials: E
authors.lastname: Bergeron
authors.forename: Nathalie
authors.initials: N
authors.lastname: Faucheux
mesh_terms: D000595:Amino Acid Sequence; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055427:Growth Differentiation Factor 2 / Q000494:pharmacology*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008969:Molecular Sequence Data; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051785:Smad Proteins / Q000378:metabolism; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D055396:Bone Morphogenetic Protein 2; C100596:DLX5 protein, human; D005419:Flavonoids; D055427:Growth Differentiation Factor 2; D018398:Homeodomain Proteins; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D051785:Smad Proteins; D000076182:Sp7 Transcription Factor; C478163:SP7 protein, human; D014157:Transcription Factors; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one