重组TRAIL是极具开发前景的靶向抗肿瘤药物，但非小细胞肺癌(NSCLC)细胞对其耐受，细胞死亡受体4(DR4)表达“沉默”是产生耐受重要机制。前期研究我们从中药小分子库中筛选、发现五味子乙素能重新激活NSCLC细胞中“沉默”的DR4表达，且该过程与CHOP与Chac1相关。进一步研究发现CHOP参与DR4 mRNA上调，而Chac1能延长DR4蛋白质半衰期，由此推测五味子乙素能通过CHOP参与DR4转录，通过Chac1抑制DR4泛素化降解，最终逆转NSCLC对TRAIL耐受。为验证该推测，本研究将探索五味子乙素调节CHOP与Chac1表达、CHOP调节DR4转录、Chac1抑制DR4泛素化降解的分子机制，从而拓宽TRAIL临床适应症，为从中药五味子中发现高效低毒的抗NSCLC增敏剂奠定基础。

Recombinant TRAIL is a novel tumor-targeted protein drug, however, non-small-cell lung cancer (NSCLC) is relatively resistant to TRAIL-mediated tumor surveillance，lack of DR4 expression is a major mechanism. In our previous investigation, we established drug screening system based on death receptor 4 expression and screened small molecules library of Chinese medicine. As a result, we found schisandrin lignans were able to significantly upregulate DR4 expression and schisandrin B showed the strongest effect. Microarray experiment showed that schisandrin B increased CHOP and Chac1 expressions, further experiments revealed that CHOP is involved in schisandrin B-induced DR4 mRNA expression, while Chac1 prolonged the half-life of DR4. Based on these results, we presume that schisandrin B is able to increase CHOP-dependent DR4 transcription and inhibit ubiquitin-mediated DR4 degradation by Chac1. By the combinatory effects of CHOP and Chac1, schisandrin B recovers DR4 expression in NSCLC, thus reversing the resistance of NSCLC towards TRAIL. To test this hypothesis, we will investigate the molecular mechanism underlying the effects of schisandrin B on CHOP and Chac1 expressions, effect of CHOP on DR4 transcription, and effect of Chac1 on DR4 protein degradation in this study. The results of this study will widen the therapeutic value of TRAIL, and is beneficial to identify more potent anti-NSCLC agents from Frutus Schisandrae that have high efficacy and low toxicity.