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Depletion of mitochondrial reactive oxygen species downregulates
epithelial-to-mesenchymal transition in cervical cancer cells
#MMPMID27902484
Shagieva G
; Domnina L
; Makarevich O
; Chernyak B
; Skulachev V
; Dugina V
Oncotarget
2017[Jan]; 8
(3
): 4901-4913
PMID27902484
show ga
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 ?-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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