Abstract
Dickkopf-related protein 3 (Dkk-3) is a potential tumor suppressor reported in various cancer entities. However, we found that Dkk-3 was exceptionally upregulated in bladder cancer T24 cells. To validate the biological role of Dkk-3 other than a tumor suppressor, we examined the function of Dkk-3 in T24 cells. Gene silencing of Dkk-3 inhibited cell growth through inducing G₀/G₁ cell-cycle arrest. Furthermore, Dkk-3 knock-down caused macropinocytosis accompanied by autophagy, which were canceled in part by their inhibitors 5-(N-ethyl-N-isopropyl) amiloride (EIPA) and 3-methyladenine (3-MA). The macropinocytosis was induced by the Dkk-3 knock-down when there were sufficient extracellular nutrients. On the other hand, when the nutritional condition was poor, the autophagy was mainly induced by the Dkk-3 knock-down. These data indicated that Dkk-3 has a role in modulating macropinocytotic and autophagic pathways, a distinct function other than a Wnt antagonist.
Keywords:
Dickkopf-3; autophagy; macropinocytosis; nutrition.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Adenine / analogs & derivatives
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Adenine / pharmacology
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Amiloride / analogs & derivatives
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Amiloride / pharmacology
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Autophagy / drug effects
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Autophagy / genetics
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Chemokines
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism*
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Epithelial Cells / pathology
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G1 Phase Cell Cycle Checkpoints / drug effects
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G1 Phase Cell Cycle Checkpoints / genetics*
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Gene Expression Regulation, Neoplastic*
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Gene Silencing / drug effects
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Humans
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Intercellular Signaling Peptides and Proteins / genetics*
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Intercellular Signaling Peptides and Proteins / metabolism
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Lysosomal Membrane Proteins / genetics
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Lysosomal Membrane Proteins / metabolism
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MAP Kinase Kinase 4 / genetics
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MAP Kinase Kinase 4 / metabolism
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MicroRNAs / genetics
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MicroRNAs / metabolism
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / metabolism
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Pinocytosis / drug effects
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Pinocytosis / genetics*
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Signal Transduction
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Urinary Bladder / metabolism
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Urinary Bladder / pathology
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism
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rab5 GTP-Binding Proteins / genetics
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rab5 GTP-Binding Proteins / metabolism
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rac1 GTP-Binding Protein / genetics
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rac1 GTP-Binding Protein / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Chemokines
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DKK3 protein, human
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Intercellular Signaling Peptides and Proteins
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LAMP1 protein, human
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Lysosomal Membrane Proteins
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MIRN92 microRNA, human
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MicroRNAs
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RAC1 protein, human
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RNA, Small Interfering
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3-methyladenine
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Amiloride
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MAPK1 protein, human
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
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RAB5C protein, human
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rab5 GTP-Binding Proteins
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rac1 GTP-Binding Protein
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Adenine
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ethylisopropylamiloride