Reactive oxygen species induce epithelial‑mesenchymal transition, glycolytic switch, and mitochondrial repression through the Dlx‑2/Snail signaling pathways in MCF‑7 cells

Lee,Su  Yeon; Ju,Min  Kyung; Jeon,Hyun  Min; Lee,Yig  Ji; Kim,Cho  Hee; Park,Hye  Gyeong; Han,Song  Iy; Kang,Ho  Sung

doi:10.3892/mmr.2019.10466

Reactive oxygen species induce epithelial‑mesenchymal transition, glycolytic switch, and mitochondrial repression through the Dlx‑2/Snail signaling pathways in MCF‑7 cells

Authors:
- Su Yeon Lee
- Min Kyung Ju
- Hyun Min Jeon
- Yig Ji Lee
- Cho Hee Kim
- Hye Gyeong Park
- Song Iy Han
- Ho Sung Kang
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Affiliations: Department of Molecular Biology, College of Natural Sciences, Pusan National University, Busan 46241, Republic of Korea, Nanobiotechnology Center, Pusan National University, Busan 46241, Republic of Korea, Division of Natural Medical Sciences, College of Health Science, Chosun University, Gwangju, Gyeonggi 61452, Republic of Korea
Published online on: July 3, 2019 https://doi.org/10.3892/mmr.2019.10466
Pages: 2339-2346

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Abstract

Reactive oxygen species (ROS) are important cellular second messengers involved in various aspects of cell signaling. ROS are elevated in multiple types of cancer cells, and this elevation is known to be involved in pathological processes of cancer. Although high levels of ROS exert cytotoxic effects on cancer cells, low levels of ROS stimulate cell proliferation and survival by inducing several pro‑survival signaling pathways. In addition, ROS have been shown to induce epithelial‑mesenchymal transition (EMT), which is essential for the initiation of metastasis. However, the precise mechanism of ROS‑induced EMT remains to be elucidated. In the present study, it was indicated that ROS induce EMT by activating Snail expression, which then represses E‑cadherin expression in MCF‑7 cells. It was further indicated that distal‑less homeobox‑2 (Dlx‑2), one of the human Dlx gene family proteins involved in embryonic development, acts as an upstream regulator of ROS‑induced Snail expression. It was also revealed that ROS treatment induces the glycolytic switch, a phenomenon whereby cancer cells primarily rely on glycolysis instead of mitochondrial oxidative phosphorylation for ATP production, even in the presence of oxygen. In addition, ROS inhibited oxidative phosphorylation and caused cytochrome c oxidase inhibition via the Dlx‑2/Snail cascade. These results suggest that ROS induce EMT, the glycolytic switch and mitochondrial repression by activating the Dlx‑2/Snail axis, thereby playing crucial roles in MCF‑7 cancer cell progression.

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