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PMID: 15169915 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Akt mediates Ras downregulation of RhoB, a suppressor of transformation, invasion, and metastasis.

Molecular and cellular biology ·Vol. 24 ·No. 12 ·2004-06-00 ·Pages 5565-76

Jiang K, Sun J, Cheng J, Djeu JY, Wei S, Sebti S

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.

MeSH Terms
Animals Antimetabolites, Antineoplastic/pharmacology Cell Transformation, Neoplastic/genetics,metabolism Down-Regulation Female Fluorouracil/pharmacology Genes, ras MAP Kinase Signaling System/drug effects Melanoma, Experimental/genetics,prevention & control,secondary Mice Mice, Inbred C57BL NIH 3T3 Cells Neoplasm Invasiveness Neoplasm Metastasis Phosphatidylinositol 3-Kinases/metabolism Promoter Regions, Genetic/drug effects Protein Serine-Threonine Kinases Proto-Oncogene Proteins/metabolism Proto-Oncogene Proteins c-akt Transcription, Genetic ras Proteins/metabolism rhoB GTP-Binding Protein/genetics,metabolism
Chemicals
Antimetabolites, Antineoplastic Proto-Oncogene Proteins Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt ras Proteins rhoB GTP-Binding Protein Fluorouracil
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Jiang Kun
Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, and Department of Interdisciplinary Oncology, University of South Florida, Tampa, 33612, USA.
Sun Jiazhi
Cheng Jin
Djeu Julie Y
Wei Sheng
Sebti Saïd
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.24.12.5565-5576.2004
Published
2004-06-00
Pages
5565-76
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC419878
Subset
IM
Grants
NCI NIH HHS · U19 CA067771 · United States
NCI NIH HHS · CA67771 · United States
External Links
PubMed source DOI: 10.1128/MCB.24.12.5565-5576.2004 PMC Full Text View journal details
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