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Reactive oxygen species mediate oxaliplatin-induced epithelial-mesenchymal transition and invasive potential in colon cancer

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Tumor Biology

Abstract

Therapeutic benefits offered by common chemotherapy drugs, such as oxaliplatin, are limited due to the development of resistance, which contributes to treatment failure and metastasis. The epithelial-mesenchymal transition (EMT) is a key event contributing to the development of resistance to chemotherapeutics. Although the relationship between oxaliplatin and chemotherapy resistance has been described for decades, the molecular mechanisms have remained elusive. The aim of the present study was to investigate the underlying mechanisms of oxaliplatin-mediated metastasis. Here, we identify reactive oxygen species (ROS) as mediators that promote the oxaliplatin-induced EMT. Following oxaliplatin treatment, the messenger RNA (mRNA) levels of most peroxiredoxin family genes, except for peroxiredoxin 1 (prdx1) gene, were constant or even decreased, resulting in ROS abundance. And the antioxidant guardian Nrf2 was unconspicuously raised both transcriptionally and translationally with oxaliplatin treatment as compared to those induced by topotecan treatment, which has been proved with no induced metastasis. In addition, the study evaluated high levels of ROS leading to EMT via activation of the known oncogenes Akt and Snail. Using the Akt inhibitor LY294002 or knocking down Snail expression via RNA interference (RNAi) reversed the effects of oxaliplatin on the EMT and metastasis. Our studies establish a role for the ROS-Akt-Snail axis as a mechanism by which chemotherapeutics induce EMT and cancer metastasis.

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Abbreviations

CRC:

colorectal cancer

EMT:

epithelial-mesenchymal transition

NAC:

N-acetyl-L-cysteine

ROS:

reactive oxygen species

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Acknowledgments

This work was supported by grants from the National Nature Science Foundation of China (81272341), the Fundamental Research Funds for the Central Universities (12ykpy50), and the Pearl River Nova Program of Guangzhou (2014J220039).

Authors’ contributions

LJ carried out the immunoassays, performed the statistical analysis, and drafted the manuscript. D-DL carried out the microscope observation and flow cytometry assay and participated in the design of the study. C-LY, R-QP, and Y-QG participated in the immunohistochemistry assay. X-SZ and X-FZ conceived of the study and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.

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    Authors and Affiliations

    1. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, 651 Dongfeng Road East, Guangzhou, 510060, China

      Lin Jiao, Dan-Dan Li, Chen-Lu Yang, Rui-Qing Peng, Yi-Qun Guo, Xiao-Shi Zhang & Xiao-Feng Zhu

    2. Department of Biotherapy, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, China

      Dan-Dan Li, Rui-Qing Peng, Yi-Qun Guo & Xiao-Shi Zhang

    3. Department of Gynecologic Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, China

      Chen-Lu Yang

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    1. Lin Jiao
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    Correspondence to Xiao-Shi Zhang or Xiao-Feng Zhu.

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    All human experiments complied with ethical regulations and were approved by the medical ethics subcommittee of Sun Yat-sen University.

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    Lin Jiao and Dan-Dan Li contributed equally to this work.

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    Suppl Fig. 1

    Oxaliplatin Induced EMT and Invasion (a) HCT116 cells were treated with five clinical drugs for indicated concentration respectively. E-cadherin and Vimentin expression were examined by western blotting. (b) the migrating numbers of cells treated with five clinical drugs were counted, respectively (mean ± SD in three separate experiments in triplicates). (GIF 131 kb)

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    Jiao, L., Li, DD., Yang, CL. et al. Reactive oxygen species mediate oxaliplatin-induced epithelial-mesenchymal transition and invasive potential in colon cancer. Tumor Biol. 37, 8413–8423 (2016). https://doi.org/10.1007/s13277-015-4736-9

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