Preventing MEK1 activation influences the responses of human osteosarcoma cells to bone morphogenetic proteins 2 and 9

Park, Hyunjin^a; Drevelle, Olivier^a; Daviau, Alex^a; Senta, Helena^a,b; Bergeron, Eric^a,c; Faucheux, Nathalie^a,b

^aDepartment of Chemical Engineering and Biotechnological Engineering, Laboratory of Cell-Biomaterial Biohybrid Systems, University of Sherbrooke

^bEtienne LeBel Clinical Research Center, Sherbrooke University Hospital Centre (CHUS), Sherbrooke

^cDepartment of Physics Engineering, Laboratory of Laser Processing and Plasmonics, Ecole Polytechnique de Montréal, Montréal, Québec, Canada

Correspondence to Nathalie Faucheux, Department of Chemical Engineering and Biotechnological Engineering, Université de Sherbrooke, 2500 boulevard de l'Université, Sherbrooke, Québec, J1K 2R1, Canada Tel: +1 819 821 8000 61343; fax: +1 819 821 7955; e-mail:[email protected]

Received June 11, 2012

Accepted November 17, 2012

Anti-Cancer Drugs24(3):p 278-290, March 2013. |DOI:10.1097/CAD.0b013e32835cbde7

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 ofdistal-less homeobox 5 andOsterix mRNAs in SaOS-2 cells within 6 h, whereas pBMP-9 had no effect. PD98059 promoted the highest level ofOsterix 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.