BMP2 accelerates the motility and invasiveness of gastric cancer cells via activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway.
Up-regulation of bone morphogenetic proteins (BMPs) and their receptors by tumor is an important hallmark in cancer progression, as it contributes through autocrine and paracrine mechanisms to tumor development, invasion, and metastasis. Generally, increased motility and invasion are positively correlated with the epithelial-mesenchymal transition (EMT). The purpose of the present study was to determine whether BMP-2 signaling to induce gastric cancer cells to undergo EMT-mediated invasion might pass through the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Herein we showed that gastric cancer cell lines express all the components of BMP-2 signaling, albeit to different extents. Moreover, an increased concentration of BMP-2 strongly enhanced motility and invasiveness in gastric cancer cells, whereas no increase was observed in cells treated with either Noggin (a BMP-2 inhibitor) or BMP-2 blocking antibodies. The stimulation of BMP-2 in gastric cancer cells induces a full EMT characterized by Snail induction, E-cadherin delocalization and down-regulation, and up-regulation of mesenchymal and invasiveness markers. Furthermore, blockade of BMP-2 signaling by Noggin or BMP-2 blocking antibodies also restored these changes in EMT markers. In addition, phosphorylation of Akt was also enhanced by treatment with BMP-2, but not Noggin or BMP-2 blocking antibodies. Pretreatment of gastric cancer cells with PI-3 kinase/Akt kinase inhibitor (kinase-dead Akt [DN-Akt], Akt siRNA, or LY294002) significantly inhibited BMP-2-induced EMT and invasiveness. Overall, our studies suggest that BMP-2 promotes motility and invasion of gastric cancer cells by activating PI-3 kinase/Akt and that targeting of this signaling pathway may provide therapeutic opportunities in preventing metastasis mediated by BMP-2.
Kang
Myoung Hee
MH
Graduate School of Medicine, Korea University College of Medicine, Korea University, Seoul 136-705, Korea.
Kim
Jun Suk
JS
Seo
Ji Eun
JE
Oh
Sang Cheul
SC
Yoo
Young A
YA
D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D055396:Bone Morphogenetic Protein 2 / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000502:physiology*; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000494:pharmacology; D052004:Bone Morphogenetic Protein Receptors / Q000235:genetics; D015820:Cadherins / Q000378:metabolism; D002352:Carrier Proteins / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D003094:Collagen; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D015870:Gene Expression / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D007797:Laminin; D009025:Morpholines / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D009419:Nerve Tissue Proteins / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011509:Proteoglycans; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology*; D014157:Transcription Factors / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism; D000099176:Noggin Protein
D000906:Antibodies; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D052004:Bone Morphogenetic Protein Receptors; D015820:Cadherins; D002352:Carrier Proteins; D002867:Chromones; D003094:Collagen; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D038362:Glycogen Synthase Kinase 3; D007797:Laminin; D009025:Morpholines; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011509:Proteoglycans; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D051785:Smad Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D014746:Vimentin; D000099176:Noggin Protein; C091514:BABAM2 protein, human; C525718:BMP2 protein, human; C525809:BMP4 protein, human; C059485:matrigel; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one