期刊
REDOX BIOLOGY
卷 17, 期 -, 页码 224-235出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.redox.2018.04.020
关键词
5-FU resistance; DNA demethylase; DUOX2; Epithelial-mesenchymal transition; Metastasis
资金
- Basic Research Laboratory Program by the National Research Foundation of Korea [NRF] - Korea government [NRF-2017R1A4A1014512]
- Science and Technology Amicable Relationships by the National Research Foundation of Korea [NRF] - Korea government [NRF-2017K1A3A1A21013557]
- National Research Foundation of Korea [NRF] - Korea government [NRF-2016R1A2B4007934]
- R&D Program of Plasma Advanced Technology for Agriculture and Food (Plasma Farming) via the National Fusion Research Institute of Korea (NFRI) - Korea Government
- National Research Foundation of Korea [2017K1A3A1A21013557] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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, SNUCS/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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