RPS15A介导自噬效应在海生素治疗白血病中的分子机制

Leukemia is a hematopoietic system malignant tumor, it characteristic with dangerously ill. The severe chemotherapy side effects and drug resistance is common. It is urgently need to look for anti-cancer drugs with effective anticancer activity, no obvious side effects and not easily formation of drug resistance. HSS is a potential new drug for leukemia treatment which extracted from marine Tegillarca granosa. We have reported its cytotoxicity effect on leukemia cells in previous studies. This effect was mediated by autophagy and found that RPS15A is the effector molecule in our later repeated studies. Based on above study, the present study focus on target molecules and the downstream regulated networks to further investigate the regulated mechanism of RPS15A on autophagy. Furthermore, the regulated mechanism of HSS on RPS15A and autophagy will be verified in leukemic nude mouse models, to reveal the mechanisms of HSS on leukemia killing and provide a theoretical basis for it be leukemia drug in the future.

白血病是造血系统的恶性肿瘤，病情凶险，化疗副作用大且耐药现象普遍，寻找具备有效抗癌活性、无明显毒副作用且不易产生耐药的抗癌药是亟待解决的问题。自泥蚶（Tegillarca granosa）提取的海生素（HSS）是治疗白血病的潜力新药。申请者在前期研究中已报道了海生素对白血病细胞的杀伤作用，并在后期通过多重实验发现、验证其作用是通过自噬效应所介导，且此过程的效应分子是RPS15A。在此基础上，本项目拟从靶标分子和下游调控网络两方面深入研究RPS15A对自噬的调控机制，并在白血病裸鼠模型中验证HSS对RPS15A、自噬的调控，由此揭示HSS对白血病杀伤作用的机制，为其成为治疗白血病药物提供理论基础。

白血病是造血系统的恶性肿瘤，病情凶险，化疗副作用大且耐药现象普遍，课题组前期发现海生素对白血病细胞和动物模型有一定杀伤作用，为了深入了解其相关分子机制，本项目在前期基础上，通过MTT检测、扫描电镜观察自噬小体以及裸鼠白血病模型检测等实验方法，从细胞和动物层面进一步证实了海生素有效治疗白血病的效果，明确海生素抑制细胞增殖、促进细胞凋亡、抑制细胞自噬是通过下调RPS15A的表达而实现，发现PI3K缓解了RPS15A引起的细胞凋亡，PI3K的激活剂740Y-P逆转了RPS15A的作用，进而深入揭示了PI3K/Akt/mTOR 信号通路参与海生素-RPA15A的功能发挥。通过上述研究，本项目明确了海生素-RPS15A对自噬的调控机制，揭示了海生素-RPS15A-自噬调节轴为有效治疗白血病提供了潜在靶点及实验依据，也为后继研究提供了潜在方向。