Abstract
In the course of cancer progression, epithelial cells often acquire morphological and functional characteristics of mesenchymal cells, a process known as epithelial-to-mesenchymal transition (EMT). EMT provides epithelial cells with migratory, invasive, and stem cell capabilities. Reactive oxygen species produced by mitochondria (mtROS) could be of special importance for pro-tumorigenic signaling and EMT.In our study, we used mitochondria-targeted antioxidant SkQ1 to lower the mtROS level and analyze their role in the regulation of the actin cytoskeleton, adhesion junctions, and signaling pathways critical for tumorigenesis of cervical carcinomas. A decrease in mtROS was found to induce formation of β-cytoplasmic actin stress fibers and circumferential rings in cervical cancer SiHa and Ca-Ski cells. It was accompanied by an upregulation of E-cadherin in SiHa cells and a downregulation of N-cadherin in Ca-Ski cells. In SiHa cells, an increase in E-cadherin expression was accompanied by a reduction of Snail, E-cadherin negative regulator. A stimulation of mtROS by epidermal growth factor (EGF) caused a Snail upregulation in SiHa cells that could be downregulated by SkQ1. SkQ1 caused a decrease in activation of extracellular-signal-regulated kinases 1 and 2 (ERK1/2) in SiHa and Ca-Ski. EGF produced an opposite effect. Incubation with SkQ1 suppressed EGF-induced p-ERK1/2 upregulation in SiHa, but not in Ca-Ski cells. Thus, we showed that scavenging of mtROS by SkQ1 initiated reversal of EMT and suppressed proliferation of cervical cancer cells.
Highlights
Functioning of epithelial tissues requires stable intercellular contacts and cell polarity
Cytoplasmic actins are organized in different cytoskeletal structures and connected to distinct cell junctions. β-Actin is predominant in stress fibers, circular bundles, contractile mitotic rings, and adhesion junctions (AJ). γ-Actin is connected to tight junctions [28] and is organized in cortical and lamellar networks [29]
The antiproliferative action of SkQ1 could be mediated by reorganization of β-actin cytoskeleton and inhibition of mitogen-activated protein kinases (MAPK) signaling in cervical cancer cells
Summary
Functioning of epithelial tissues requires stable intercellular contacts and cell polarity. Strict tissue organization is lost in epithelial tumors. Tumor epithelial cells usually discard basoapical polarity and reorganize cytoskeleton and adhesion junctions to acquire morphological and functional characteristics of mesenchymal cells. This process is known as EMT [1, 2]. EMT molecular changes include a downregulation of epithelial markers, such as E-cadherin, alpha-catenin and keratins, as well as a rise in expression of mesenchymal proteins N-cadherin and vimentin. Escaping from the epithelial environment allows oncogene-expressing cells to proliferate and evolve [8]
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