1、解螺旋陪伴医生科研成长 1 自噬与肿瘤细胞耐药自噬与肿瘤细胞耐药 本综述由解螺旋学员 旺 负责修订（2018 年 10 月）自噬（autophagy）是不同于凋亡的一种细胞死亡编程1-3。它是指胞质内双层膜包裹部分胞质和细胞内需降解的细胞器、蛋白质等成分形成自噬体（autophagosome），并与溶酶体融合形成自噬溶酶体，降解其所包裹内容物的过程4-6。自噬一方面为细胞本身代谢和某些细胞器更新提供能源；另一方面当细胞处于应激（如内质网应激、氧化应激和饥饿等）过剩状态时，细胞通过自噬方式“自杀”诱导细胞凋亡7。自噬的发生和发展和多种疾病都有联系，包括炎症、肿瘤和耐药8。解螺旋 研究发现，肿瘤细
2、胞在受到化疗药物刺激时，自噬信号通路被激活，自噬水平提高，从而分解这些药物分子，提高其自身对药物敏感性，促进细胞存活9。Juan Wang 等人研究发现激活 ERK/MAPK 信号可以提高自噬水平，从而加强卵巢癌细胞对顺铂的耐药性10;YANG X 等观察到缺氧诱导的自噬可以促进人膀胱癌细胞对吉西他滨的耐药11；相反，抑制自噬可以增加肿瘤细胞对化疗药物（如伊马替尼、紫杉醇、铂类药物和 5-氟尿嘧啶等）敏感性。体外实验表明乳腺癌细胞中凋亡关键因子的缺失和下调，以及自噬机制的激活可能是紫杉醇耐药的主要机制12，文献报道 p38 和 JNK/MAPK 通路在调控自噬和凋亡的平衡中起重要角色13。随着
3、研究不断进展，人们发现许多 microRNA（如 mir-155、miR-376b、miR-30a、miR-874）也可以通过抑制自噬加强癌细胞对化疗药物敏感性14-16。但是也有文献报道激活自噬会增强肿瘤细胞对药物的敏感性。Sirichanchuen 等人用顺铂和三氟拉嗪（自噬激活剂）同时处理肺癌耐药细胞株以后能够抑制肺癌耐药17。Zhou 课题组研究发现 mTOR 抑制剂和 Bacl-2 抑制剂可以通过激活乳腺癌细胞自噬方式增强乳腺癌对化疗药物敏感性，进一步证明自噬激活可以增强乳腺癌细胞药物敏感性18。解螺旋 细胞自噬在肿瘤细胞耐药过程中的作用具有两面性。自噬促进细胞生存还是死亡依赖于肿瘤
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