title: Inhibition of Stat3 signaling pathway by nifuroxazide improves antitumor immunity and impairs colorectal carcinoma metastasis.
abstract: Colorectal carcinoma (CRC) is the one of the most common cancers with considerable metastatic potential, explaining the need for new drug candidates that inhibit tumor metastasis. The signal transducers and activators of the transcription 3 (Stat3) signaling pathway has an important role in CRC and has been validated as a promising anticancer target for CRC therapy. In the present study, we report our findings on nifuroxazide, an antidiarrheal agent identified as an inhibitor of Stat3. Our studies showed that nifuroxazide decreased the viability of three CRC cell lines and induced apoptosis of cancer cells in a concentration-dependent manner. Moreover, western blot analysis demonstrated that the occurrence of its apoptosis was correlated with the activation of Bax and cleaved caspase-3, and decreased the expression of Bcl-2. In addition, nifuroxazide markedly impaired CRC cell migration and invasion by downregulating phosphorylated-Stat3Tyr705, and also impaired the expression of matrix metalloproteinases (MMP-2 and MMP-9). Furthermore, our studies showed that nifuroxazide also significantly inhibited the tumor metastasis in lung and abdomen metastasis models of colon cancer. Meanwhile, nifuroxazide functionally reduced the proliferation index, induced tumor apoptosis and impaired metastasis. Notably, nifuroxazide reduced the number of myeloid-derived suppressor cells in the blood, spleens and tumors, accompanied by the increased infiltration of CD8+T cells in the tumors. Importantly, a marked decrease in the number of M2-type macrophages in tumor in the abdomen metastasis model was also observed. Taken together, our results indicated that nifuroxazide could effectively inhibit tumor metastasis by mediating Stat3 pathway and it might have a therapeutic potential for the treatment of CRC.
authors.affiliation: Department of Liver Surgery and Division of Digestive Diseases, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Ting-Hong
authors.initials: TH
authors.lastname: Ye
authors.affiliation: Department of Liver Surgery and Division of Digestive Diseases, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Fang-Fang
authors.initials: FF
authors.lastname: Yang
authors.affiliation: Department of Liver Surgery and Division of Digestive Diseases, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Yong-Xia
authors.initials: YX
authors.lastname: Zhu
authors.affiliation: Department of Liver Surgery and Division of Digestive Diseases, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Ya-Li
authors.initials: YL
authors.lastname: Li
authors.affiliation: Department of Liver Surgery and Division of Digestive Diseases, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Lei
authors.affiliation: Department of Liver Surgery and Division of Digestive Diseases, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Xue-Jiao
authors.initials: XJ
authors.lastname: Song
authors.affiliation: Department of Liver Surgery and Division of Digestive Diseases, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Liver Surgery and Division of Digestive Diseases, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.|Department of Pharmacy, Xinqiao Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Department of Liver Surgery and Division of Digestive Diseases, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Li-Dan
authors.initials: LD
authors.lastname: Zhang
authors.affiliation: Department of Liver Surgery and Division of Digestive Diseases, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Ning-Yu
authors.initials: NY
authors.lastname: Wang
authors.affiliation: Department of Liver Surgery and Division of Digestive Diseases, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Li-Feng
authors.initials: LF
authors.lastname: Zhao
authors.affiliation: Department of Abdominal Cancer, Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Hong-Feng
authors.initials: HF
authors.lastname: Gou
authors.affiliation: Department of Liver Surgery and Division of Digestive Diseases, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Yong-Mei
authors.initials: YM
authors.lastname: Xie
authors.affiliation: Department of Liver Surgery and Division of Digestive Diseases, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Sheng-Yong
authors.initials: SY
authors.lastname: Yang
authors.affiliation: Department of Liver Surgery and Division of Digestive Diseases, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Luo-Ting
authors.initials: LT
authors.lastname: Yu
authors.affiliation: Department of Liver Surgery and Division of Digestive Diseases, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Liver Surgery and Division of Digestive Diseases, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, China.
authors.forename: Yu-Quan
authors.initials: YQ
authors.lastname: Wei
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D062385:Hydroxybenzoates / Q000008:administration & dosage; D051379:Mice; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009581:Nitrofurans / Q000008:administration & dosage; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D062385:Hydroxybenzoates; D009363:Neoplasm Proteins; D009581:Nitrofurans; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C013150:nifuroxazide