Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibodies / immunology
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Antibodies / pharmacology
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Bone Morphogenetic Protein 2 / antagonists & inhibitors
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Bone Morphogenetic Protein 2 / pharmacology
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Bone Morphogenetic Protein 2 / physiology*
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Bone Morphogenetic Protein 4 / genetics
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Bone Morphogenetic Protein 4 / pharmacology
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Bone Morphogenetic Protein Receptors / genetics
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Cadherins / metabolism
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Carrier Proteins / pharmacology
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Cell Line, Tumor / drug effects
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Cell Movement / drug effects
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Cell Movement / physiology*
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Cell Proliferation / drug effects
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Chromones / pharmacology
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Collagen
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Drug Combinations
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Enzyme Inhibitors
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Gene Expression / genetics
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Genes, Reporter / genetics
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Glycogen Synthase Kinase 3 / metabolism
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Humans
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Laminin
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Morpholines / pharmacology
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Neoplasm Invasiveness*
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Nerve Tissue Proteins / genetics
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Phosphatidylinositol 3-Kinases / metabolism*
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation / drug effects
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Proteoglycans
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Proto-Oncogene Proteins c-akt / metabolism*
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RNA, Small Interfering / genetics
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Signal Transduction / physiology*
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Smad Proteins / metabolism
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Snail Family Transcription Factors
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Stomach Neoplasms / metabolism
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Stomach Neoplasms / pathology*
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Transcription Factors / metabolism
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Vimentin / metabolism
Substances
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Antibodies
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BABAM2 protein, human
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BMP2 protein, human
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BMP4 protein, human
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Bone Morphogenetic Protein 2
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Bone Morphogenetic Protein 4
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Cadherins
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Carrier Proteins
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Chromones
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Drug Combinations
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Enzyme Inhibitors
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Laminin
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Morpholines
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Nerve Tissue Proteins
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Phosphoinositide-3 Kinase Inhibitors
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Proteoglycans
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RNA, Small Interfering
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Smad Proteins
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Snail Family Transcription Factors
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Transcription Factors
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Vimentin
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matrigel
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noggin protein
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Collagen
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Proto-Oncogene Proteins c-akt
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Glycogen Synthase Kinase 3
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Bone Morphogenetic Protein Receptors