新型小分子化合物乙烷硒啉通过抑制TrxR1活性下调p65表达促进非小细胞肺癌凋亡机制的研究

研究报道,课题组成员参与研发的新型小分子化合物乙烷硒啉能通过抑制TrxR1活性发挥抗肿瘤作用。我们前期研究发现：与癌旁组织相比，50%的NSCLC患者癌组织TrxR1高表达且活性增高，同时伴随转录因子p65的表达上调；BBSKE能通过抑制TrxR1活性诱导A549细胞凋亡，但其抗肺癌机制有待进一步研究。为此，本课题拟通过免疫组化和siRNA技术分析TrxR1高表达在NSCLC发生中的作用；进一步利用细胞转染、免疫蛋白印迹、核浆分离和免疫共沉淀技术，研究TrxR1通过增加Trx还原能力上调p65表达，促进肺癌细胞增殖、抑制凋亡的机制；最后以在体实验证实BBSKE能够通过抑制TrxR1活性、下调p65表达进而抑制肿瘤生长、延长荷瘤小鼠存活时间。研究结果不仅有助于揭示BBSKE抗NSCLC的机制，并将为BBSKE成为NSCLC潜在的靶向治疗药物提供理论基础和实验依据。

Research reported that a novel small molecule compound Ethaselen had been shown to exert anti-tumor effect by inhibiting TrxR1 activity .We found that TrxR1 highly expressed in 50% of patients in NSCLC tissues. Our group members were involved in the research of novel compound Ethaselen which was shown to exert anti-tumor effects by downregulating TrxR1 activity. We intent to find the occurrence mechanism of TrxR1 by immunohistochemistry in NSCLC, and further using western blot and co-immunoprecipitation by siRNA to provide the evidence of TrxR1 regulated p65 expression and promotes NSCLC cancer cells proliferation and anti-apoptosis through maintaining the possibility of Trx; Finally, we want to confirm that BBSKE can inhibit tumor growth and prolong the survival time of xenografts mice in vivo by down-regulating the activity of p65 through inhibiting the activity of TrxR1. This finding will firstly clarify the molecular mechanism of anti-NSCLC of BBSKE, providing powerful evidences that BBSKE can promote NSCLC cell apoptosis in NSCLC cells and it will be a theoretical basis for the targeted therapy of NSCLC.