title: Depletion of mitochondrial reactive oxygen species downregulates epithelial-to-mesenchymal transition in cervical cancer cells.
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.
authors.affiliation: Department of Mathematical Methods in Biology, Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Galina
authors.initials: G
authors.lastname: Shagieva
authors.affiliation: Department of Mathematical Methods in Biology, Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Lidiya
authors.initials: L
authors.lastname: Domnina
authors.affiliation: Faculty of Basic Medicine, Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Olga
authors.initials: O
authors.lastname: Makarevich
authors.affiliation: Department of Bioenergetics, Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Boris
authors.initials: B
authors.lastname: Chernyak
authors.affiliation: Department of Bioenergetics, Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.|Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Skulachev
authors.affiliation: Department of Mathematical Methods in Biology, Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Vera
authors.initials: V
authors.lastname: Dugina
mesh_terms: D000199:Actins / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010971:Plastoquinone / Q000031:analogs & derivatives* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000071250:Snail Family Transcription Factors / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000378:metabolism*
chemical_list: C532038:10-(6'-plastoquinonyl)decyltriphenylphosphonium; D000199:Actins; D000970:Antineoplastic Agents; D015820:Cadherins; D017382:Reactive Oxygen Species; D000071250:Snail Family Transcription Factors; D010971:Plastoquinone
keywords: ERK1/2; SkQ1; cervical cancer cells; epithelial-to-mesenchymal transition; mitochondrial reactive oxygen species