title: 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 β-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 β-catenin in gastric cancer cells. These results indicate that rhBMP-2 attenuated the growth of gastric cancer cells via the inactivation of β-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.
authors.affiliation: Department of Orthopaedic Surgery, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, 561-180, Republic of Korea.
authors.forename: Kwang Bok
authors.initials: KB
authors.lastname: Lee
authors.affiliation: Department of Physiology, Chonbuk National University Medical School, Jeonju, 561-180, Republic of Korea.
authors.forename: Hua
authors.initials: H
authors.lastname: Jin
authors.affiliation: Department of Orthopaedic Surgery, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University-Biomedical Research Institute of Chonbuk National University Hospital, Jeonju, 561-180, Republic of Korea.
authors.forename: Shuai
authors.initials: S
authors.lastname: Ye
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School, Jeonju, 561-180, Republic of Korea.
authors.forename: Byung Hyun
authors.initials: BH
authors.lastname: Park
authors.affiliation: Department of Physiology, Chonbuk National University Medical School, Jeonju, 561-180, Republic of Korea.
authors.forename: Soo Mi
authors.initials: SM
authors.lastname: Kim
mesh_terms: D064127:Aurora Kinases / Q000378:metabolism*; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D051785:Smad Proteins / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D016271:Proto-Oncogene Proteins c-myc; D011994:Recombinant Proteins; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2; D064127:Aurora Kinases
keywords: AURKA; AURKB; Myc; gastric cancer cell; rhBMP-2