Recombinant human bone morphogenetic protein-2 inhibits gastric cancer cell proliferation by inactivating Wnt signaling pathway via c-Myc with aurora kinases

Abstract

The detailed molecular mechanisms and safety issues of recombinant human bone morphogenetic protein-2 (rhBMP-2) usage in bone graft substitution remain poorly understood. To investigate the molecular mechanisms underlying the function of rhBMP-2 in gastric cancer cells, we used microarrays to determine the gene expression patterns related to the effects of rhBMP-2. Based on a gene ontology analysis, several genes were upregulated during the regulation of the cell cycle and BMP signaling pathway. MYC was found to be significantly decreased along with its downstream target genes, the aurora kinases (AURKs), by rhBMP-2 in the network analysis. We further confirmed this finding with western blot data that rhBMP-2 inhibited c-Myc, AURKs, and beta-catenin in SNU484 and SNU638 cells. An AURK inhibitor significantly decreased c-Myc expression in gastric cancer cells. Combination treatment with rhBMP-2 and AURK inhibitor resulted in significantly decreased c-Myc expression compared with gastric cancer cells treated with an rhBMP-2 or AURK inhibitor, respectively. Similar effects for decreased c-Myc expression were observed when we silenced beta-catenin in gastric cancer cells. These results indicate that rhBMP-2 attenuated the growth of gastric cancer cells via the inactivation of beta-catenin via c-Myc and AURKs. Therefore, our findings suggest that rhBMP-2 could be safely used with patients who undergo gastric or gastroesophageal cancer surgery.