PO.MCB02.01 · 分子与细胞生物学
靶向ULK1克服癌细胞中自噬介导的化疗耐药
Targeting ULK1 overcomes autophagy-mediated chemoresistance in cancer cell
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
自噬是一种受到严格调控、依赖溶酶体的循环利用过程，可在应激状态下维持能量平衡与蛋白稳态，从而促进细胞存活。尽管化疗旨在清除恶性细胞，许多肿瘤却通过启动促存活自噬获得耐药性。为阻断这一逃逸途径，我们靶向了Unc-51样激酶1（ULK1）——自噬体生物合成的起始因子。我们通过对已报道的ULK1抑制剂骨架进行修饰构建了一个化合物库，并利用LC3-GFP-mCherry串联报告系统筛选对自噬流的阻断作用。Western blot验证了靶向性抑制作用，包括磷酸化ATG13的减少与p62的累积，据此提名了一种新型先导化合物。在多种癌细胞系中，将该化合物与标准化疗药物联合使用，伴随自噬流的减弱，细胞死亡增加。这些数据支持ULK1作为克服自噬介导化疗耐药的可干预节点，并为将ULK1抑制作为深化化疗反应的联合策略提供了合理依据。未来研究将评估其体内抗肿瘤疗效与耐受性，以推动这一新型ULK1抑制剂进入临床前开发阶段。
查看英文原文 English abstract
Autophagy is a tightly regulated, lysosomedependent recycling process that preserves energy balance and proteostasis during stress, thereby promoting cell survival. Although chemotherapy aims to eliminate malignant cells, many tumors acquire resistance by engaging prosurvival autophagy. To disable this escape, we targeted Unc51like kinase 1 (ULK1), the initiator of autophagosome biogenesis. We generated a library by modifying reported ULK1 inhibitor scaffolds and screened for blockade of autophagic flux using an LC3GFPmCherry tandem reporter. Western blotting verified ontarget suppression, including phosphorylated ATG13 reduction and p62 accumulation, which nominated a novel lead compound. By treating this compound with standard chemotherapeutics in multiple cancer cell lines, cell death was increased concomitant with the blunted autophagic flux. These data support ULK1 as a tractable node to overcome autophagymediated chemoresistance and rationalize ULK1 inhibition as a combination strategy to deepen chemotherapy responses. Future study will evaluate antitumor efficacy and tolerability in vivo to advance a novel ULK1 inhibitor toward preclinical development.
利益披露 Disclosure
E. Kim, None..
Y. Park, None.