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Article Dans Une Revue Redox Biology Année : 2018

DUOX2-mediated production of reactive oxygen species induces epithelial mesenchymal transition in 5-fluorouracil resistant human colon cancer cells

Résumé

The therapeutic benefits offered by 5-fluorouracil (5-FU) are limited because of the acquisition of drug resistance, the main cause of treatment failure and metastasis. The ability of the cancer cells to undergo epithelial-mesenchymal transition (EMT) contributes significantly to cancer metastatic potential and chemo-resistance. However, the underlying molecular mechanisms of 5-FU-resistance have remained elusive. Here, we show that reactive oxygen species (ROS), produced by dual oxidase 2 (DUOX2), promote 5-FU-induced EMT. First, we showed that 5-FU-resistant SNUC5 colon cancer cells (SNUC5/FUR cells) undergo EMT by analyzing the expression of EMT markers such as N-cadherin, vimentin and E-cadherin. In addition, we found that the resistant cells expressed higher levels of Snail, Slug, Twist and Zeb1, which are all critical EMT regulators and had enhanced migratory and invasive capabilities. Furthermore, SNUC5/FUR cells had increased level of DUOX2, resulting in increased ROS level. This effect was due to the enhanced binding of the ten eleven translocation 1 (TET1) demethylase to the DUOX2 promoter in the SNUC5/FUR cells. Importantly, silencing of TET1 reversed the effects of 5-FU on the cells. Finally, the antioxidant N-acetylcysteine attenuated the effects of 5-FU on EMT and metastasis. Our study demonstrates the existence of a TET1/DUOX2/ROS/EMT axis that could play a role in colon cancer chemo-resistance and the aggressiveness of this cancer.
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hal-01802361 , version 1 (01-06-2021)

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Kyoung Ah Kang, Yea Seong Ryu, Mei Jing Piao, Kristina Shilnikova, Hee Kyoung Kang, et al.. DUOX2-mediated production of reactive oxygen species induces epithelial mesenchymal transition in 5-fluorouracil resistant human colon cancer cells. Redox Biology, 2018, 17, pp.224 - 235. ⟨10.1016/j.redox.2018.04.020⟩. ⟨hal-01802361⟩
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