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

新型硫氧还蛋白还原酶抑制剂丁烷硒啉通过下调PD-L1的表达来抑制肿瘤的发生（英文）

The thioredoxin system plays a role in a variety of physiological functions, including cell growth, differenti- ation, 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-CD8^＋ 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.

目的:评估新型硫氧还蛋白还原酶抑制剂丁烷硒啉(BS)对小鼠免疫系统及肿瘤发生的影响,并初步探讨其作用机制。创新点:实验室自主设计的硫氧还蛋白还原酶抑制剂BS对免疫系统的调节作用及机制探究。方法:将24只体重为18~22g的正常雄性KM小鼠随机分为4组,分别为BS低、中、高剂量组和对照组,每组6只动物。于接种小鼠肝癌H22细胞(1×106个/只)后第2天开始给药,给药剂量分别为:空白对照组(5g/L羧甲基纤维素钠(CMC-Na),灌胃(i.g.),每日一次(q.d.));BS低剂量组(90mg/kg,i.g.,q.d.);BS中剂量组(180mg/kg,i.g.,q.d.);BS高剂量组(360 mg/kg,i.g.,q.d.)。每天观察小鼠状态,连续8天。结论:BS通过促进小鼠脾淋巴细胞的活化来抑制肿瘤增殖。BS能够通过下调体内肿瘤细胞表面的程序性死亡配体1(PD-L1)的表达,提高小鼠CD4^-CD8^+T淋巴细胞百分比和下游细胞因子的分泌。在HepG2和BEL-7402细胞中的进一步研究表明,通过抑制信号传导子及转录激活子3(STAT3)磷酸化,BS处理后PD-L1表达水平降低。综上所述,BS通过STAT3途径降低PD-L1表达,从而产生促进免疫应答的作用,抑制肿瘤发生。