Inhibition of Stat3 signaling pathway by nifuroxazide improves antitumor immunity and impairs colorectal carcinoma metastasis

• Published in: Cell death & disease Vol. 8; no. 1; p. e2534
• Main Authors: Ye, Ting-Hong, Yang, Fang-Fang, Zhu, Yong-Xia, Li, Ya-Li, Lei, Qian, Song, Xue-Jiao, Xia, Yong, Xiong, Ying, Zhang, Li-Dan, Wang, Ning-Yu, Zhao, Li-Feng, Gou, Hong-Feng, Xie, Yong-Mei, Yang, Sheng-Yong, Yu, Luo-Ting, Yang, Li, Wei, Yu-Quan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.01.2017; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/2; 13/51; 13/95; 631/67/1059/99; 631/67/1504/1885; 631/67/322; 631/80/86; Animals; Antibiotics; Antibodies; Apoptosis; Apoptosis - genetics; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell Line, Tumor; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Gene Expression Regulation, Neoplastic - drug effects; Humans; Hydroxybenzoates - administration & dosage; Immunology; Life Sciences; Metastasis; Mice; Neoplasm Metastasis - drug therapy; Neoplasm Metastasis - genetics; Neoplasm Proteins - biosynthesis; Nitrofurans - administration & dosage; Original; original-article; Signal Transduction - drug effects; STAT3 Transcription Factor - antagonists & inhibitors; STAT3 Transcription Factor - genetics; Xenograft Model Antitumor Assays
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2016.452

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-Stat3 Tyr705 , 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.