Rocaglamide enhances NK cell-mediated killing of non-small cell lung cancer cells by inhibiting autophagy
Rocaglamide enhances NK cell-mediated killing of non-small cell lung cancer cells by inhibiting autophagy
复制标题
罗卡酰胺通过抑制自噬增强 NK 细胞介导的非小细胞肺癌细胞杀伤作用
DOI：
10.1080/15548627.2018.1489946
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发表时间：
2018-01-01
期刊：
影响因子：
13.3
通讯作者：
Zhu, Shiguo
中科院分区：
文献类型：
--
作者：
Yao, Chao;Ni, Zhongya;Zhu, Shiguo
摘要 靶向巨自噬/自噬是癌症免疫治疗的一种新策略。在本研究中，我们发现天然产物罗卡酰胺（RocA）可增强自然杀伤（NK）细胞介导的体外非小细胞肺癌（NSCLC）细胞裂解作用和体内肿瘤消退作用。而且，这种效应与NK细胞对靶细胞的识别或死亡受体的表达无关。相反，RocA 抑制自噬并恢复 NSCLC 细胞中 NK 细胞衍生的 GZMB（颗粒酶 B）的水平，从而增加其对 NK 细胞介导的杀伤的敏感性。此外，我们进一步确定了 RocA 的靶点是自噬启动所需的 ULK1（unc-51 样自噬激活激酶 1）。使用含有 ULK1 5´ 非翻译区的萤火虫荧光素酶，我们发现 RocA 以序列特异性方式抑制 ULK1 的蛋白质翻译。综上所述，RocA 可以阻断自噬免疫对 NK 细胞介导的杀伤的抵抗，我们的数据表明，RocA 是基于 NK 细胞的癌症免疫疗法中很有前途的候选治疗药物。
ABSTRACT Targeting macroautophagy/autophagy is a novel strategy in cancer immunotherapy. In the present study, we showed that the natural product rocaglamide (RocA) enhanced natural killer (NK) cell-mediated lysis of non-small cell lung cancer (NSCLC) cells in vitro and tumor regression in vivo. Moreover, this effect was not related to the NK cell recognition of target cells or expressions of death receptors. Instead, RocA inhibited autophagy and restored the level of NK cell-derived GZMB (granzyme B) in NSCLC cells, therefore increasing their susceptibility to NK cell-mediated killing. In addition, we further identified that the target of RocA was ULK1 (unc-51 like autophagy activating kinase 1) that is required for autophagy initiation. Using firefly luciferase containing the 5´ untranslated region of ULK1, we found that RocA inhibited the protein translation of ULK1 in a sequence-specific manner. Taken together, RocA could block autophagic immune resistance to NK cell-mediated killing, and our data suggested that RocA was a promising therapeutic candidate in NK cell-based cancer immunotherapy.