Akt mediates Ras downregulation of RhoB, a suppressor of transformation, invasion, and metastasis.
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.
Jiang
Kun
K
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
J
Cheng
Jin
J
Djeu
Julie Y
JY
Wei
Sheng
S
Sebti
Saïd
S
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D011905:Genes, ras; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008546:Melanoma, Experimental / Q000235:genetics / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D014158:Transcription, Genetic; D018631:ras Proteins / Q000378:metabolism*; D020743:rhoB GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism*
D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins; D020743:rhoB GTP-Binding Protein