靶向氨基酸转运体4F2hc对肺癌放疗疗效的影响和机制研究

放疗是肺癌患者重要的治疗选择之一，然而部分患者会产生耐受。mTORC1信号通路在肺癌中常见异常激活，其激活后增加肿瘤干细胞干性是导致放疗抵抗的重要原因。氨基酸转运体通过调节氨基酸摄入在mTORC1信号通路中发挥重要作用，然而靶向氨基酸转运体是否增强肺癌放疗疗效未见报道。我们发现氨基酸转运体4F2hc在肺癌放疗抵抗的细胞和组织中表达增强，敲减4F2hc可显著增强放疗引起的细胞死亡。进一步研究发现4F2hc可以和调节mTORC1活性的蛋白v-ATPase以一种氨基酸刺激依赖的方式结合。据此我们推测：在肺癌患者体内高表达的4F2hc通过v-ATPase活化mTORC1信号通路对放疗产生抵抗，靶向4F2hc可增强肺癌患者对放疗的敏感性。本课题将首先明确4F2hc在肺癌放疗中的作用和机制，另外我们将筛选出靶向4F2hc的小分子药物，通过细胞和动物模型探讨靶向4F2hc在克服肺癌放疗抵抗中的可行性。

Radiation therapy is one of the most frequent treatment for lung cancer patients. However, most of the patients will be resistant to the treatment. Activation of mTORC1 pathway contributes to the development of resistance to the radiation therapy. Although amino acids transporters hold a critical role in mTORC1 activation through amino acids uptake, whether targeting amino acids has benefit to lung cancer radiation therapy is unknown. Our preliminary studies indicated that amino acids transporter 4F2hc was highly expressed in lung cancer cells and tissues which were resistant to radiation therapy. Consistently, knockdown of 4F2hc can significantly promote radiation therapy induced cell death. We further found 4F2hc interacted with mTORC1 regulatory protein v-ATPase in an amino acids dependent manner. According to these date, we hypothesize that the highly expressed 4F2hc in lung cancer cells lead to the resistance to the radiation therapy through interacting with v-ATPase to activate mTORC1 signaling, and targeting 4F2hc helps to overcome the radiation therapy resistance. In this study, we will investigate the role and mechanism of 4F2hc in mTORC1 activation and lung cancer radiation therapy in cultured cancer cells and cancer tissue sections. Furthermore, we will screen the small molecular drugs targeting 4F2hc,and evaluate the effect of this small molecular drugs in lung cancer radiation therapy in cells and mouse models.