Abstract
The small GTPase Rac1 has been implicated in a variety of dynamic cell biological processes, including cell proliferation, cell survival, cell-cell contacts, epithelial mesenchymal transition (EMT), cell motility, and invasiveness. These processes are orchestrated through the fine tuning of Rac1 activity by upstream cell surface receptors and effectors that regulate the cycling Rac1-GDP (off state)/Rac1-GTP (on state), but also through the tuning of Rac1 accumulation, activity, and subcellular localization by post translational modifications or recruitment into molecular scaffolds. Another level of regulation involves Rac1 transcripts stability and splicing. Downstream, Rac1 initiates a series of signaling networks, including regulatory complex of actin cytoskeleton remodeling, activation of protein kinases (PAKs, MAPKs) and transcription factors (NFkB, Wnt/β-catenin/TCF, STAT3, Snail), production of reactive oxygen species (NADPH oxidase holoenzymes, mitochondrial ROS). Thus, this GTPase, its regulators, and effector systems might be involved at different steps of the neoplastic progression from dysplasia to the metastatic cascade. After briefly placing Rac1 and its effector systems in the more general context of intestinal homeostasis and in wound healing after intestinal injury, the present review mainly focuses on the several levels of Rac1 signaling pathway dysregulation in colorectal carcinogenesis, their biological significance, and their clinical impact.
Highlights
Colorectal cancer (CRC) is a major cause of cancer morbidity and mortality in western countries.Nearly 140,000 and 450,000 individuals are diagnosed annually in United-States and in Europe, where this cancer is responsible of approximately 53,000 and 215,000 related deaths, respectively [1,2].Colorectal cancers arise through the stepwise accumulation of genetic alterations, including the activation/overexpression of a series of-oncogenes, and the inactivation of tumor suppressor genes [3,4] and follow three molecular pathways to genome instability characterized by (i) chromosomal instability (CIN), (ii) high microsatellite instability (MSI-H), or (iii) CpG island methylator phenotype (CIMP)
These GTPases act as binary switches from active GTP (Guanosine triphosphate)-bound form, that interacts with effector molecules to initiate signaling, to the GDP (Guanosine diphosphate)-bound inactive form
High levels of Rac1-GTP were evidenced in colorectal cancerous tissues compared to control mucosa and these levels were significantly correlated with TNM stages, lymph node spread, and distant metastasis as well as patient survival [89]
Summary
Colorectal cancer (CRC) is a major cause of cancer morbidity and mortality in western countries. Rac initiates several signaling pathways, -including PAKs, NOX1 complex/reactive oxygen species (ROS) production, NFkB, members of MAPKs, Wnt/β-catenin/TCF, STAT3-, regulating membrane ruffling, cytoskeletal remodeling, cell adhesion, cell–cell contacts, cell polarity, cell motility, and transcriptional activity, leading to cell proliferation, epithelial mesenchymal transition (EMT), and invasiveness (Figure 2). This GTPase might be involved at different steps of the neoplastic progression from dysplasia to the metastatic cascade. Cancer cell invasiveness might involve individual (mesenchymal, amoeboid) or multi-cellular mode of migration. Rac interacting partners and downstream effectors: transcription factors are represented in brown, effector molecules in black, pathways involved in cytoskeleton remodeling and cell migration in blue, and ROS pathway in Red
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