Abstract
Recently, it has been demonstrated that macrophage inflammatory protein 1- alpha (MIP-1 alpha) is crucially involved in the development of osteolytic bone lesions in multiple myeloma (MM). The current study was designed to determine the direct effects of MIP-1 alpha on MM cells. Thus, we were able to demonstrate that MIP-1 alpha acts as a potent growth, survival, and chemotactic factor in MM cells. MIP-1 alpha-induced signaling involved activation of the AKT/protein kinase B (PKB) and the mitogen-activated protein kinase (MAPK) pathway. In addition, inhibition of AKT activation by phosphatidylinositol 3- kinase (PI3-K) inhibitors did not influence MAPK activation, suggesting that there is no cross talk between MIP-1 alpha-dependent activation of the PI3-K/AKT and extracellular-regulated kinase (ERK) pathway. Our data suggest that besides its role in development of osteolytic bone destruction, MIP-1 alpha also directly affects cell signaling pathways mediating growth, survival, and migration in MM cells and provide evidence that MIP-1 alpha might play a pivotal role in the pathogenesis of MM.
MeSH terms
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Androstadienes / pharmacology
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Cell Division
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Cell Survival
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Chemokine CCL3
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Chemokine CCL4
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Cytokines / metabolism
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Enzyme Activation
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Enzyme Inhibitors / pharmacology
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Flavonoids / pharmacology
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Humans
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MAP Kinase Kinase 1
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MAP Kinase Signaling System / physiology
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Macrophage Inflammatory Proteins / physiology*
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mitogen-Activated Protein Kinases / metabolism
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Multiple Myeloma / metabolism
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Multiple Myeloma / pathology*
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Neoplasm Proteins / metabolism
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Osteolysis / metabolism
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Phosphatidylinositol 3-Kinases / physiology
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation
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Protein Processing, Post-Translational
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / physiology
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Proto-Oncogene Proteins c-akt
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Receptors, Chemokine / metabolism
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Signal Transduction / physiology*
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Tumor Cells, Cultured / cytology
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Tumor Cells, Cultured / metabolism
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Wortmannin
Substances
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Androstadienes
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Chemokine CCL3
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Chemokine CCL4
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Cytokines
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Enzyme Inhibitors
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Flavonoids
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Macrophage Inflammatory Proteins
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Neoplasm Proteins
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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Receptors, Chemokine
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macrophage inflammatory protein 1alpha receptor
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 1
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MAP2K1 protein, human
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Mitogen-Activated Protein Kinase Kinases
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
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Wortmannin