Novel thioredoxin reductase inhibitor butaselen inhibits tumorigenesis by down-regulating programmed death-ligand 1 expression

• Published in: Journal of Zhejiang University. B. Science Vol. 19; no. 9; pp. 689 - 698
• Main Authors: Zou, Qiao, Chen, Yi-fan, Zheng, Xiao-qing, Ye, Suo-fu, Xu, Bin-yuan, Liu, Yu-xi, Zeng, Hui-hui
• Format: Journal Article
• Language: English
• Published: Hangzhou Zhejiang University Press 01.09.2018; Springer Nature B.V
• Subjects: Animals; Anticancer properties; Antineoplastic Agents - pharmacology; Apoptosis; B7-H1 Antigen - antagonists & inhibitors; Biomedical and Life Sciences; Biomedicine; Cancer; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - drug effects; Cell activation; Cytokines; Hep G2 Cells; Humans; Immune response; Immune system; Immunity; In vivo methods and tests; Inhibitors; Ligands; Liver Neoplasms - drug therapy; Liver Neoplasms - pathology; Lymphocytes; Lymphocytes T; Male; Mice; Organoselenium Compounds - pharmacology; PD-L1 protein; Phosphorylation; Reductase; Spleen; Stat3 protein; STAT3 Transcription Factor - physiology; Thioredoxin; Thioredoxin-Disulfide Reductase - antagonists & inhibitors; Transcription; Tumor Burden - drug effects; Tumor cell lines; Tumor cells; Tumorigenesis; Tumors; Signal transducer and activator of transcription 3 (STAT3); 丁烷硒啉; 免疫; Butaselen; 信号传导子及转录激活子3(STAT3); 硫氧还蛋白 还原酶; Programmed death-ligand 1 (PD-L1); Immunity; Thioredoxin reductase; 程序性死亡配体1(PD-L1); R73; Butaselen; Signal transducer and activator of transcription 3 (STAT3); Programmed death-ligand 1 (PD-L1); Immunity; Thioredoxin reductase
• ISSN: 1673-1581; 1862-1783
• DOI: 10.1631/jzus.B1700219

The thioredoxin system plays a role in a variety of physiological functions, including cell growth, differentiation, apoptosis, tumorigenesis, and immunity. We previously confirmed that butaselen (BS), a novel thioredoxin reductase inhibitor, can inhibit the growth of various human cancer cell lines, yet the underlying mechanism remains elusive. In this study, we investigated the anti-tumor effect of BS in vivo through regulating the immune system of KM mice. We found that BS inhibits tumor proliferation by promoting the activation of splenic lymphocytes in mice. BS can elevate the percentage of CD 4 − CD 8 + T lymphocytes and the secretion of downstream cytokines in mice via downregulating the expression of programmed death-ligand 1 (PD-L1) on the tumor cells’ surface in vivo. Further study in HepG2 and BEL-7402 cells showed that decrease of PD-L1 level after BS treatment was achieved by inhibiting signal transducer and activator of transcription 3 (STAT3) phosphorylation. Taken together, our results suggest that BS has a role in promoting the immune response by reducing PD-L1 expression via the STAT3 pathway, and subsequently suppresses tumorigenesis.