TrxR1介导mTOR抑制剂耐药及其联合作用诱导胃癌细胞凋亡的机制研究

The discovery of new target and new drug candidates for the treatment of gastric cancer is of great significance. A large number of studies have found that mTOR signaling pathway was over activated in gastric cancer. However, clinical studies have shown that useing mTOR inhibitor alone does not reach a good anti gastric cancer effect. TrxR1 is the critical enzyme in regulating the redox balance in vivo, and our previous studies found that TrxR1 was overexpressed in human gastric cancer cells and clinical tissues. Furthermore, we found that mTOR inhibitor rapamycin could significantly increase the expression and activity of TrxR1 in human gastric cancer cells, and TrxR1 inhibitor could enhance the chemosensitivity of gastric cancer cells to rapamycin. Therefore, we hypothesize that TrxR1 mediates the resistance of mTOR inhibitor on gastric cancer cells. The project plans to identify that inhibition of TrxR1 can reverse the drug resistance of gastric cancer cells to mTOR inhibitor, and elucidate the molecular mechanisms of the combined effects of TrxR1 inhibitor and mTOR inhibitor at the cellular level. We will use subcutaneous xenografts and PDTX model to fully validate the effects and mechanism of the combined treatment at the animal level; At the clinical level, we plan to analysis the clinical relevance of gastric cancer with the expressions of p-mTOR and TrxR1. The project will confirm that TrxR1 mediates the drug resistance of gastric cancer cells to mTOR inhibitor, and elucidate the molecular mechanism of combined action in anti gastric cancer, provide a new drug combination and idea for clinical treatment of gastric cancer.

胃癌新靶点和新药物发现具有重要的意义。研究发现mTOR信号通路在胃癌中过度激活，然而临床研究表明mTOR抑制剂并不能达到很好的抗胃癌效果。TrxR1是体内调节氧化还原平衡的重要蛋白，我们前期研究发现其在胃癌中过表达。进一步研究发现mTOR抑制剂雷帕霉素会明显的上调胃癌细胞中TrxR1的表达和活性，且TrxR1抑制剂能够显著增敏雷帕霉素的促凋亡效果。因此，我们推测TrxR1介导了胃癌细胞对mTOR抑制剂的耐药。本项目拟在细胞层面上确证抑制TrxR1能够逆转胃癌细胞对mTOR抑制剂的耐药，阐明TrxR1和mTOR抑制剂联合作用的分子机制；动物层面上利用细胞皮下移植瘤和PDTX模型，充分验证联合作用的效果和机制；临床层面上分析p-mTOR和TrxR1与胃癌的临床相关性。本项目将确证TrxR1介导了胃癌细胞对mTOR抑制剂的耐药，阐明联合作用抗胃癌的分子机制，为临床治疗胃癌提供新的药物组合和思路。

胃癌和结肠癌是常见的消化道恶性肿瘤，目前临床尚无很好的治疗药物，因此寻找一种新的药物或者药物组合具有非常重要的研究价值和临床意义。本研究在胃癌和结肠癌细胞上确证了TrxR1抑制剂增敏mTOR抑制剂的作用效果，并阐明了联合作用的分子机制。发现TrxR1抑制剂Auranofin能够显著增敏mTOR抑制剂的抗肿瘤活性。机制研究发现Auranofin能够协同mTOR抑制剂上调细胞中的ROS水平，从而激活下游内质网应激和JNK信号通路，来发挥其联合抗肿瘤作用。在此基础上，本研究进一步在动物层面确证了联合作用的效果和分子机制。发现Auranofin联合Everolimus具有很强的体内抗肿瘤活性，小鼠的肿瘤体积不但没有变大，反而在联合给药后显著变小。动物体重数据和HE数据均表明Auranofin与Everolimus联合具有良好的体内安全性。这个发现具有比较重要的临床意义，因为Auranofin与Everolimus都是FDA批准应用于临床的药物，这两个药物的组合能够展现如此优秀的抗肿瘤活性，以及较好的安全性，这为这两个药物组合进一步应用于临床提供了理论依据。此外，依托于本项目我们发现了几个新的TrxR1抑制剂。总之，本研究阐明了TrxR1抑制剂增敏mTOR抑制剂的效果和分子机制，为临床治疗胃癌和结肠癌提供了新的候选药物组合和理论依据。