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: Hyunjin Park, Olivier Drevelle, Alex Daviau, Helena Senta, Eric Bergeron, Nathalie Faucheux
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 24 Issue 3 Pg. 278-90 (Mar 2013) ISSN: 1473-5741 [Electronic] England
• PMID: 23262982 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bone Morphogenetic Protein 2
• DLX5 protein, human
• Flavonoids
• Growth Differentiation Factor 2
• Homeodomain Proteins
• Peptide Fragments
• Protein Kinase Inhibitors
• Smad Proteins
• Sp7 Transcription Factor
• Sp7 protein, human
• Transcription Factors
• Mitogen-Activated Protein Kinase 3
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 1
• MAP2K1 protein, human
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one

Topics

• Amino Acid Sequence
• Bone Morphogenetic Protein 2 (pharmacology)
• Bone Neoplasms (drug therapy, genetics, metabolism, pathology)
• Dose-Response Relationship, Drug
• Flavonoids (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Growth Differentiation Factor 2 (pharmacology)
• Homeodomain Proteins (genetics)
• Humans
• MAP Kinase Kinase 1 (antagonists & inhibitors, metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Molecular Sequence Data
• Osteosarcoma (drug therapy, genetics, metabolism, pathology)
• Peptide Fragments (pharmacology)
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Smad Proteins (metabolism)
• Sp7 Transcription Factor
• Transcription Factors (genetics)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)