title: Reactive oxygen species mediate oxaliplatin-induced epithelial-mesenchymal transition and invasive potential in colon cancer.
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.
authors.affiliation: 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.
authors.forename: Lin
authors.initials: L
authors.lastname: Jiao
authors.affiliation: 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.|Department of Biotherapy, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, China.
authors.forename: Dan-Dan
authors.initials: DD
authors.lastname: Li
authors.affiliation: 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.|Department of Gynecologic Oncology, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, China.
authors.forename: Chen-Lu
authors.initials: CL
authors.lastname: Yang
authors.affiliation: 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.|Department of Biotherapy, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, China.
authors.forename: Rui-Qing
authors.initials: RQ
authors.lastname: Peng
authors.affiliation: 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.|Department of Biotherapy, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, China.
authors.forename: Yi-Qun
authors.initials: YQ
authors.lastname: Guo
authors.affiliation: 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. zhangxsh@sysucc.org.cn.|Department of Biotherapy, Cancer Center, Sun Yat-sen University, Guangzhou, 510060, China. zhangxsh@sysucc.org.cn.
authors.forename: Xiao-Shi
authors.initials: XS
authors.lastname: Zhang
authors.affiliation: 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. zhuxfeng@mail.sysu.edu.cn.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D009025:Morpholines / Q000494:pharmacology; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D054464:Peroxiredoxins / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D000071250:Snail Family Transcription Factors / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D002867:Chromones; D009025:Morpholines; D009944:Organoplatinum Compounds; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D000071250:Snail Family Transcription Factors; D000077150:Oxaliplatin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D054464:Peroxiredoxins; D051057:Proto-Oncogene Proteins c-akt
keywords: Colorectal cancer; EMT; Invasion; Migration; Nrf2; Oxaliplatin; Peroxiredoxin; ROS