Research Papers:

Depletion of mitochondrial reactive oxygen species downregulates epithelial-to-mesenchymal transition in cervical cancer cells

Galina Shagieva _, Lidiya Domnina, Olga Makarevich, Boris Chernyak, Vladimir Skulachev and Vera Dugina

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Oncotarget. 2017; 8:4901-4913. https://doi.org/10.18632/oncotarget.13612

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Galina Shagieva1, Lidiya Domnina1, Olga Makarevich2, Boris Chernyak3, Vladimir Skulachev3,4, Vera Dugina1

1Department of Mathematical Methods in Biology, Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia

2Faculty of Basic Medicine, Lomonosov Moscow State University, Moscow, Russia

3Department of Bioenergetics, Belozersky Research Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow, Russia

4Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, Russia

Correspondence to:

Galina Shagieva, email: gshagieva@genebee.msu.su

Keywords: epithelial-to-mesenchymal transition, mitochondrial reactive oxygen species, ERK1/2, cervical cancer cells, SkQ1

Received: July 22, 2016     Accepted: November 14, 2016     Published: November 25, 2016


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.

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