Requirement for Rac1 in a K-ras–Induced Lung Cancer in the Mouse

Abstract

Given the prevalence of Ras mutations in human cancer, it is critical to understand the effector pathways downstream of oncogenic Ras leading to transformation. To directly assess the requirement for Rac1 in K-ras-induced tumorigenesis, we employed a model of lung cancer in which an oncogenic allele of K-ras could be activated by Cre-mediated recombination in the presence or absence of conditional deletion of Rac1. We show that Rac1 function is required for tumorigenesis in this model. Furthermore, although Rac1 deletion alone was compatible with cell viability and proliferation, when combined with K-ras activation in primary epithelial cells, loss of Rac1 caused a profound reduction in proliferation. These data show a specific requirement for Rac1 function in cells expressing oncogenic K-ras. [Cancer Res 2007;67(17):8089-94]

Increased Rac1b Expression Sustains Colorectal Tumor Cell Survival

“…The antiapoptotic function of Rac1 signaling has already previously been found essential for experimental cell transformation (8,9,32) or mouse tumor models (10,11). On the other hand, Rac1 signaling may also promote apoptosis in certain cell types and this can involve the activation of the downstream c-Jun-NH 2 -kinase cascade in intestinal epithelial cells (36) or of the p38 mitogen-activated protein kinase (37,38).…”

“…3, 4), which initiates an antiapoptotic transcriptional response and also promotes cell cycle progression by an increase in cyclin D1 expression (4)(5)(6). Rac signaling was shown to be essential for the transformation of cultured cells (7)(8)(9) and for tumor formation in vivo (10,11), underlining that deregulated Rac1 activation is involved in tumor progression (12).…”

Rac1 is crucial for Ras-dependent skin tumor formation by controlling Pak1-Mek-Erk hyperactivation and hyperproliferation in vivo

“…Indeed, altering Rac1 activation in a colon cancer cell line regulated tumor formation in mice (Espina et al, 2008) and deletion of the Rac1 gene in lung epithelium inhibited K-Ras-induced lung tumors (Kissil et al, 2007). The manner how Rac1 affects proliferation and apoptosis during tumorigenesis in vivo, however, was not studied.…”

“…In a colorectal carcinoma model involving orthotopic injection of adenocarcinoma cells into mice, Rac1 overexpression promoted, and Rac1 knockdown decreased tumor progression (Espina et al, 2008). More recently, activation of Rac proteins was described to be crucial for the development of chronic myelogenous leukemia (Thomas et al, 2007) and K-Ras-induced lung cancer (Kissil et al, 2007). Indirect evidence also suggested a role for Rac1 in skin tumor formation, as mice lacking the Rac1-specific GEF Tiam1, which display about 50% reduction in GTP-bound Rac1, are rather resistant to 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin tumor formation (Malliri et al, 2002).…”

The role of Rac1 in the regulation of NF-kB activity, cell proliferation, and cell migration in non-small cell lung carcinoma

“…1,2 The importance of Rac1 in neoplastic transformation is indicated by the finding that Rac1 is necessary for K-Ras-induced transformation of fibroblasts as well as the development of K-Ras-induced lung cancer in mice. [3][4][5] Rac1 is overexpressed in breast, colon and lung carcinomas, [6][7][8][9] and increased expression of Rac1 is correlated with poor prognosis in non-small cell lung cancer (NSCLC). 10 These and other findings highlight the roles of Rac1 in neoplastic transformation, tumor progression and metastasis.…”