Abstract
Rho GDP dissociation inhibitor 2 (RhoGDI2) promotes tumor growth and malignant progression and enhances chemoresistance of gastric cancer. Recently, we noted an inverse correlation between RhoGDI2 and 14-3-3σ expression, which suggests that 14-3-3σ is a target of gastric cancer metastasis and the chemoresistance-promoting effect of RhoGDI2. Herein, we evaluated whether 14-3-3σ is regulated by RhoGDI2 and is functionally important for the RhoGDI2-induced cisplatin resistance of gastric cancer cells. We used highly metastatic and cisplatin-resistant RhoGDI2-overexpressing SNU-484 cells and observed decreased 14-3-3σ mRNA and protein expression. Depletion of 14-3-3σ in SNU-484 control cells enhanced cisplatin resistance, whereas restoration of 14-3-3σ in RhoGDI2-overexpressing SNU-484 cells impaired cisplatin resistance in vitro and in vivo. We also found that the phosphorylation levels of Erk and p38 kinases significantly decreased in RhoGDI2-overexpressing SNU-484 cells and recovered after 14-3-3σ expression, and that decreased activities of these kinases were critical for RhoGDI2-induced cisplatin resistance. In conclusion, 14-3-3σ is a RhoGDI2-regulated gene that appears to be important for suppressing the chemoresistance of gastric cancer cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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14-3-3 Proteins / biosynthesis
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14-3-3 Proteins / genetics
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14-3-3 Proteins / metabolism*
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Apoptosis / physiology
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Biomarkers, Tumor / biosynthesis
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism*
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Cell Line, Tumor
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Cell Movement / physiology
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Cisplatin / pharmacology*
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Disease Progression
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Down-Regulation
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Drug Resistance, Neoplasm
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Enzyme Activation
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Exoribonucleases / biosynthesis
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Exoribonucleases / genetics
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Exoribonucleases / metabolism*
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / metabolism*
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HeLa Cells
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Humans
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MAP Kinase Signaling System
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MCF-7 Cells
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Neoplasm Metastasis
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RNA, Small Interfering / administration & dosage
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RNA, Small Interfering / genetics
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Stomach Neoplasms / drug therapy*
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Stomach Neoplasms / genetics
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Stomach Neoplasms / metabolism*
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Stomach Neoplasms / pathology
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Transfection
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / metabolism*
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rho Guanine Nucleotide Dissociation Inhibitor beta / genetics
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rho Guanine Nucleotide Dissociation Inhibitor beta / metabolism*
Substances
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14-3-3 Proteins
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ARHGDIB protein, human
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Biomarkers, Tumor
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RNA, Small Interfering
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rho Guanine Nucleotide Dissociation Inhibitor beta
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Extracellular Signal-Regulated MAP Kinases
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p38 Mitogen-Activated Protein Kinases
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Exoribonucleases
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SFN protein, human
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Cisplatin