二甲双胍诱导分子伴侣介导自噬抑制非小细胞肺癌的功能和机制研究

Chaperone-mediated autophagy is known as an important selective autophagy. Scientists recently demonstrated that chaperone-mediated autophagy is involved in regulating cancers, but little is known about the mechanism. Meanwhile there is lack of safe and efficient chaperone mediated autophagy induers, which can be potential clinical drugs. We previously screened 1443 FDA approved drugs using High Throughput Screening, we found that metformin is a potential chaperone-mediated autophagy inducer. Using Mass Spectrometry, we identified that PD-L1 is a potential substrate of chaperone-mediated autophagy. Based on the preliminary results, we will demonstrate that metformin is a novel potent chaperone-mediated autophagy inducer, we will confirm that PD-L1 is a novel substrate of chaperone-mediated autophagy, and we will address the mechanism that metformin inhibits non-small cell lung cancer by reducing HK2, EGFR, and PD-L1 through chaperone mediated autophgy. This project will provide metformin as a novel potent chaperone-mediated autophagy inducer, delineate the novel mechanism regulating chaperone-mediated autophagy，and reveal the potential novel mechanism of metformin inhibiting non-small cell lung cancer.

分子伴侣介导自噬是一种重要的选择性自噬。近年来人们发现分子伴侣介导自噬和肿瘤等重大疾病密切相关，但其调控机制尚待进一步明确。同时我们还缺少能安全有效诱导分子伴侣介导自噬，有临床应用前景的工具小分子。根据前期实验结果，我们构建了高通量药物筛选模型，从1443个FDA批准的药物中发现二甲双胍可能参与了分子伴侣介导自噬的调控，运用生物质谱技术我们发现PD-L1可能是新的分子伴侣介导自噬底物。本项目拟在前期实验基础上，明确二甲双胍是新的分子伴侣介导自噬诱导小分子，鉴定PD-L1是新的分子伴侣介导自噬底物，阐明二甲双胍通过诱导分子伴侣介导自噬降解HK2、EGFR、PD-L1等关键蛋白抑制非小细胞肺癌的机制。本研究结果将为分子伴侣介导自噬研究提供新的工具小分子，并对其调控机制提出新的创新性见解，为应用二甲双胍治疗非小细胞肺癌提供新的科学依据。

非小细胞肺癌是一种恶性肿瘤，占所有肺癌的70%以上。二甲双胍（metformin）是一种治疗糖尿病的药物，被发现对非小细胞肺癌有抑制作用，但机制一直不清楚。我们通过实验鉴定，metformin 是分子伴侣介导自噬（chaperone mediated autophagy，CMA）新的诱导剂；我们发现metformin可以通过TAK1-IKKα/β-Hsc70新通路诱导CMA；最后我们利用动物实验证明，metformin通过诱导CMA降解HK2、EGFR等肿瘤关键蛋白，从而抑制非小细胞肺癌。本课题为应用Metformin 治疗非小细胞肺癌提供新的科学依据，有较高的科学意义和潜在临床应用价值。