Arsenic trioxide-mediated suppression of miR-182-5p is associated with potent anti-oxidant effects through up-regulation of SESN2
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Liang-Ting Lin1,10,*, Shin-Yi Liu2,*, Jyh-Der Leu3,4,*, Chun-Yuan Chang1, Shih-Hwa Chiou5,6,7, Te-Chang Lee7,8 and Yi-Jang Lee1,9
1Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan
2Department of Radiation Oncology, MacKay Memorial Hospital, Taipei, Taiwan
3Division of Radiation Oncology, Taipei City Hospital Ren Ai Branch, Taipei, Taiwan
4Institute of Neuroscience, National Chengchi University, Taipei, Taiwan
5Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan
6Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
7Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan
8Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
9Biophotonics and Molecular Imaging Research Center (BMIRC), National Yang-Ming University, Taipei, Taiwan
10Current address: Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong
*These authors have contributed equally to this work
Te-Chang Lee, email: [email protected]
Yi-Jang Lee, email: [email protected]
Keywords: arsenic trioxide; sestrin 2; miR-182; oxidative stress; anti-oxidant effect
Received: April 12, 2017 Accepted: February 24, 2018 Published: March 23, 2018
Arsenic trioxide (ATO) is a traditional Chinese medicine that can induce oxidative stress for treatment of cancer cells. However, ATO may generate anti-oxidative responses to compromise the cytotoxic effect, but the underlying mechanisms remain unclear. Here we found that ATO could inhibit miR-182-5p expression in patient-derived primary S1 glioblastoma (GBM) cells accompanied by up-regulation of Sestrin-2 (SESN2) mRNA, a known anti-oxidant molecule. This phenomenon was also detected in a U87MG glioma cell line, human lung adenocarcinoma H1299 cell line and A549 cell line. Pretreatment with a free radical scavenger N-acetylcysteine (NAC) reduced the oxidative stress induced by ATO. Concomitantly, ATO mediated suppression of miR-182-5p and enhancement of SESN2 expression were also compromised. The MTT assay further showed that ATO induced cytotoxicity was enhanced by transfection of miR-182-5p mimics. Overexpression of miR-182-5p mimics significantly suppressed the expression of SENS2 and a firefly luciferase reporter gene fused to 3’- untranslated region (UTR) of SESN2 mRNA. Use of ribonucleoprotein immunoprecipitation (RNP-IP), ATO mediated suppression of miR-182-5p led to the stabilization of SESN2 mRNA as a result of Argonaute-2 (AGO2) dependent gene silencing. Furthermore, high expression of miR-182-5p and low expression of SESN2 mRNA tend to be associated with longer survival of glioma or lung cancer patients using public available gene expression datasets and online tools for prediction of clinical outcomes. Taken together, current data suggest that the miR-182-5p/SENS2 pathway is involved in ATO induced anti-oxidant responses, which may be important for the design of novel strategy for cancer treatment.
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