Targeting lectin-like oxidized low-density lipoprotein receptor-1 triggers autophagic program in esophageal cancer
Targeting lectin-like oxidized low-density lipoprotein receptor-1 triggers autophagic program in esophageal cancer
复制标题
靶向凝集素样氧化低密度脂蛋白受体1触发食管癌的自噬程序
DOI：
10.1038/s41418-021-00884-y
复制
发表时间：
2021-10-05
影响因子：
12.4
通讯作者：
Wang, Lan
中科院分区：
文献类型：
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作者：
Li, Can;Liu, Fenglin;Wang, Lan
自噬是维持细胞内环境稳定的一种高度保守的分解代谢过程。然而，功能失调的自噬有助于癌症中的上下文依赖性作用。在这里，我们澄清了清道夫受体凝集素样氧化低密度脂蛋白受体-1（LOX-1）在食管癌（EC）中调节自噬的确切作用。各种癌症的综合分析显示，LOX-1在EC组织中上调最多，并且与患者的不良预后相关。LOX-1的离体和体内缺失通过诱导自噬性细胞死亡抑制EC发展。活化C激酶受体1（Receptor for activated C kinase 1，RACK 1）是LOX 1的信号适配器，参与RAS/MEK/ERK信号通路和TFEB核输出信号的调控，保护肿瘤的发生。从褐藻中提取的硫酸多糖岩藻依聚糖与LOX-1结合并介导LOX-1的蛋白酶体降解，而不是溶酶体途径，导致EC中自噬相关的细胞死亡。这些结果揭示了LOX-1对EC发展的重要贡献，并提供了基因消融或生物活性多糖作为EC治疗的有效干预。
Autophagy is a highly conserved catabolic process to maintain cellular homeostasis. However, dysfunctional autophagy contributes to a context-dependent role in cancer. Here, we clarified the exact role of autophagy modulated by the scavenger receptor lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in esophageal cancer (EC). A comprehensive analysis in various cancers displayed that LOX-1 was upregulated the most in EC tissues and associated with poor prognosis of patients. Deletion of LOX-1 ex vivo and in vivo suppresses EC development by inducing autophagic cell death. Receptor for activated C kinase 1 (RACK1) was identified as a signal adapter of LOX-1, which incented RAS/MEK/ERK pathway and TFEB nuclear export signal and safeguarded tumorigenesis. A sulfated polysaccharide fucoidan extracted from brown seaweed was found to bind with LOX-1 and mediate its proteasomal degradation but not the lysosome pathway, leading to autophagy-related cell death in EC. These results reveal a central contribution of LOX-1 to EC development and provide genetic ablation or bioactive polysaccharide as an effective intervention for EC therapy.