N-乙酰葡萄糖胺增强TRAIL诱导的非小细胞肺癌凋亡的机制研究

TRAIL specifically kills cancer cells through death receptors. However, non-small cell lung cancer (NSLC) exhibits drug resistance frequently because of aberrant death receptors. Therefore, search for a “helper” to strengthen binding of TRAIL with death receptor has become an urgent need. In preliminary study, we found that N-acetyl glucosamine (GlcNAc) was able to enhance the ability of TRAIL to kill A549 cancer cells while mRNA level of the death receptors was not changed. We assumed that GlcNAc might induce apoptosis by increasing binding affinity of the death receptor with TRAIL. Hence, we hypothesize that GlcNAc somehow enters cells and promotes O-glycosylation of the death receptors, which increases the TRAIL-induced formation of apoptosome and sensitivity of NSLC cancer cells to TRAIL. To prove the hypothesis, we will study the effect and mechanism that GlcNAc synergizes TRAIL to kill cancer cells from molecular, cellular to animal level. Through studying influence of GlcNAc on death receptor O-glycosylation and receptor activity, we will reveal the molecular mechanism that GlcNAc enhances apoptosis and provide new ideas for TRAIL to be used in treatment of NSLC.

TRAIL能够通过死亡受体特异杀伤癌细胞，但非小细胞肺癌（NSLC）常因死亡受体异常而对其产生耐药，所以寻找增强TRAIL与死亡受体结合的“助效剂”已成为急需。前期研究发现N-乙酰葡萄糖胺（GlcNAc）能够增强TRAIL 对A549癌细胞的杀伤，而细胞死亡受体mRNA水平没有明显变化。推测：GlcNAc可能增强死亡受体与TRAIL的亲和力而诱导凋亡。因而提出假设：GlcNAc通过某种途径进入细胞，促进死亡受体的O-糖基化，从而促进TRAIL诱导的凋亡起始复合体的形成，增强NSLC癌细胞对TRAIL的敏感性。为验证假设，我们将从分子、细胞和动物水平研究GlcNAc协同TRAIL对肿瘤细胞的作用效果和机制；通过研究GlcNAc对死亡受体的O-糖基化及受体活性的影响，揭示GlcNAc促凋亡的分子机制，为TRAIL在NSLC治疗中的应用提供新思路。

TRAIL能够通过死亡受体特异杀伤癌细胞，但非小细胞肺癌（NSLC）常因死亡受体异常而对其产生耐药，所以寻找增强TRAIL与死亡受体结合的“助效剂”已成为急需。N-乙酰葡萄糖胺（GlcNAc）能够增强TRAIL 对A549癌细胞的杀伤，而细胞死亡受体mRNA水平没有明显变化。推测GlcNAc可能增强死亡受体与TRAIL的亲和力而诱导凋亡。本研究锁定靶向的受体蛋白DR5展开研究，从DR5的糖基化水平入手，构建DR5过表达载体，研究DR5的o-GlcNAc糖基化水平，以及糖基化酶OGT的表达，阐释了N-乙酰葡萄糖胺促进TRAIL诱导非小细胞肺癌凋亡的作用机制。实验表明GlcNAc能够促进死亡受体的O-糖基化，从而促进TRAIL诱导的凋亡起始复合体的形成，增强NSLC癌细胞对TRAIL的敏感性。本研究从分子、细胞和动物水平研究GlcNAc协同TRAIL对肿瘤细胞的作用效果和机制；通过研究GlcNAc对死亡受体的O-糖基化及受体活性的影响，揭示GlcNAc促凋亡的分子机制，为TRAIL在NSLC治疗中的应用提供了必要的理论基础。