Abstract
Although recent evidence supports a tumor-suppressive role for the GTPase RhoB, little is known about its regulation by signal transduction pathways. Here we demonstrate that Ras downregulates RhoB expression by a phosphatidylinositol 3-kinase (PI3K)- and Akt- but not Mek-dependent mechanism. Furthermore, genetic and pharmacological blockade of PI3K/Akt results in upregulation of RhoB expression. We also provide evidence for the importance of the downregulation of RhoB in oncogenesis by demonstrating that RhoB antagonizes Ras/PI3K/Akt malignancy. Ectopic expression of RhoB, but not the close relative RhoA, inhibits Ras, PI3K, and Akt induction of transformation, migration, and invasion and induces apoptosis and anoikis. Finally, RhoB inhibits melanoma metastasis to the lung in a mouse model. These studies identify suppression of RhoB as a mechanism by which the Ras/PI3K/Akt pathway induces tumor survival, transformation, invasion, and metastasis.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antimetabolites, Antineoplastic / pharmacology
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Cell Transformation, Neoplastic / genetics*
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Cell Transformation, Neoplastic / metabolism*
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Down-Regulation
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Female
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Fluorouracil / pharmacology
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Genes, ras
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MAP Kinase Signaling System / drug effects
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Melanoma, Experimental / genetics
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Melanoma, Experimental / prevention & control
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Melanoma, Experimental / secondary
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Mice
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Mice, Inbred C57BL
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NIH 3T3 Cells
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Neoplasm Invasiveness
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Neoplasm Metastasis
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Phosphatidylinositol 3-Kinases / metabolism
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Promoter Regions, Genetic / drug effects
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt
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Transcription, Genetic
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ras Proteins / metabolism*
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rhoB GTP-Binding Protein / genetics*
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rhoB GTP-Binding Protein / metabolism*
Substances
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Antimetabolites, Antineoplastic
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Proto-Oncogene Proteins
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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ras Proteins
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rhoB GTP-Binding Protein
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Fluorouracil