Increased Rac1b Expression Sustains Colorectal Tumor Cell Survival

Abstract

The small GTPase Rac1 can stimulate various signaling pathways that contribute to cell transformation. In particular, the activation of the NFKB transcription factor initiates an antiapoptotic response and promotes cell cycle progression through increased cyclin D1 expression. As a potential oncogenic mechanism to up-regulate this pathway, the overexpression of the Rac1b splicing variant was reported in some colorectal tumors. Rac1b exists predominantly in the active GTP-bound state and selectively promotes the pathway leading to NFKB activation. Here, we studied the role of endogenous Rac1b in colorectal cancer cells. We found that depletion of Rac1b by small interfering RNAs inhibited endogenous NFKB activation and reduced cell viability to 50% within 48 hours. This reduction was due to increased apoptosis, although a reduced G 1 -S progression rate was also observed. These data show, for the first time, that colorectal cells expressing alternative spliced Rac1b also depend on Rac1b signaling to sustain their survival.

The diverse roles of Rac signaling in tumorigenesis

“…70 In addition, an alternative splice variant of Rac, Rac1b, has been shown to increase NFκB-mediated survival in fibroblasts, 71 and its expression in colorectal tumor cells also promotes survival. 72 Despite these numerous reports that Rac can promote cell survival through activation of Akt, Erk and NFκB, it has also been shown …”

RAC1b overexpression in papillary thyroid carcinoma: a role to unravel

“…Rac1b has been shown to sustain tumor cell survival in colorectal cancer (35) and to mediate epithelialmesenchymal transition (EMT), via a mechanism dependent on both RAC1b-induced ROS and matrix metalloproteinase 3 (MMP3), in mouse mammary epithelial cells (33). Uncontrolled proliferation and EMT are ultimately involved in the development of tumor formation, invasion, and metastases (36).…”

Rac1b recruits Dishevelled and β-catenin to Wnt target gene promoters independent of Wnt3A stimulation

“…Over-expression of Rac1b was recently attributed to the enhanced expression of exon 3b inclusion splice factor ASF/SF2 (10). Unlike Rac1 GTPase, Rac1b does not lead to lamellipodia formation, or the activation of PAK1, AKT1, or c-Jun-NH2-kinase activities (11). However, Rac1b retains the ability to stimulate the NFκB pathway and was shown to induce transcriptional stimulation of a consensus NFκB promoter in a luciferase reporter construct (12,13).…”

“…Rac1b is unable to bind to many regulators of Rho family GTPases, although it displays enhanced binding to SmgGDS, RACK1, and p120 catenin, proteins involved in cell-cell adhesion, motility, and transcriptional regulation (14). Rac1b signaling is essential for tumor cell viability and survival (11). Intriguingly, Rac1b also cooperates functionally with B-Raf V600E mutations to sustain colorectal cell viability suggesting that the two proteins constitute an alternative survival pathway to oncogenic K-ras in colon tumors (15).…”