EGFR, ErbB2 and Ras but not Src suppress RhoB expression while ectopic expression of RhoB antagonizes oncogene-mediated transformation.
While some low molecular weight GTPases such as Ras and RhoA contribute to malignant transformation, a closely related family member, RhoB, has tumor-suppressive activity, but little is known about its regulation by oncogenes. In this study, we show that H-Ras, N-Ras, K-Ras, EGFR and ErbB2 but not v-Src suppress RhoB promoter transcriptional activity in NIH3T3 cells and human cancer cell lines derived from lung (A-549), pancreatic (Panc-1) and cervical (C33A) tumors. The EGFR and ErbB2 suppression of RhoB promoter activity is mediated by Ras. Furthermore, Ras suppresses basal as well as 5-fluorouracil (5-FU)-induced RhoB promoter activity and RhoB protein levels. Ectopic expression of RhoB, but not the closely related family member RhoA, antagonizes the ability of EGFR, ErbB2, H-Ras, N-Ras and K-Ras but not v-Src to transform NIH3T3 cells. Furthermore, RhoB, but not RhoA, inhibits colony formation and proliferation and induces anoikis in A-549 cells and Ras-transformed NIH3T3 cells. Finally, Ras-mediated resistance to 5-FU-induced apoptosis is reversed by RhoB. These results demonstrate that RhoB expression is negatively regulated by oncogenes that are prevalent in human cancers, and that ectopic expression of RhoB antagonizes the ability of these oncogenes to induce transformation. Taken together the data suggest that certain oncogenes suppress RhoB as one of the critical steps leading to malignant transformation.
Jiang
Kun
K
Drug Discovery Program, H Lee Moffitt Cancer Center & Research Institute, Department of Interdisciplinary Oncology and Biochemistry, University of South Florida, Tampa, FL 33612, USA.
Delarue
Frederic L
FL
Sebti
Saïd M
SM
D000818:Animals; D023102:Anoikis / Q000235:genetics; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D018734:Genes, erbB-2 / Q000235:genetics / Q000502:physiology*; D011905:Genes, ras / Q000235:genetics / Q000502:physiology*; D016391:Genes, src; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics; D051379:Mice; D041681:NIH 3T3 Cells; D010190:Pancreatic Neoplasms / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000235:genetics; D020743:rhoB GTP-Binding Protein / Q000378:metabolism*
D000964:Antimetabolites, Antineoplastic; D066246:ErbB Receptors; D020743:rhoB GTP-Binding Protein; D005472:Fluorouracil