MAPK1/3 kinase-dependent ULK1 degradation attenuates mitophagy and promotes breast cancer bone metastasis
MAPK1/3 kinase-dependent ULK1 degradation attenuates mitophagy and promotes breast cancer bone metastasis
复制标题
MAPK1/3激酶依赖性ULK1降解减弱线粒体自噬并促进乳腺癌骨转移
DOI：
10.1080/15548627.2020.1850609
复制
发表时间：
2020-12-06
期刊：
影响因子：
13.3
通讯作者：
Zhu, Xiao-Feng
中科院分区：
文献类型：
--
作者：
Deng, Rong;Zhang, Hai-Liang;Zhu, Xiao-Feng
摘要 线粒体自噬在癌症中的功能存在争议。 ULK1 对于巨自噬/自噬的诱导至关重要，并且在响应缺氧的线粒体自噬中具有更具体的作用。在这里，我们发现 ULK1 缺陷会在缺氧条件下诱导乳腺癌细胞的侵袭表型并增加溶骨性骨转移。从机制上讲，ULK1 耗竭会减弱缺氧期间的线粒体自噬能力。结果，受损的、产生ROS的线粒体的积累导致NLRP3炎症小体的激活，从而诱导可溶性细胞因子的异常分泌，然后促进破骨细胞的分化和成熟，最终导致骨转移。值得注意的是，MAPK1/ERK2-MAPK3/ERK1 激酶对 ULK1 的磷酸化会触发其与 BTRC 的相互作用以及随后的 K48 相关泛素化和蛋白酶体降解。此外，在人类乳腺癌组织中观察到 ULK1 和 p-MAPK1/3 的表达水平之间存在明显的负相关。 MAP2K/MEK 抑制剂曲美替尼足以通过上调 ULK1 恢复线粒体自噬功能，从而抑制 NLRP3 炎性体激活，从而减少骨转移。这些结果表明，ULK1 敲除介导的线粒体自噬缺陷促进乳腺癌骨转移，并为探索 MAP2K/MEK-MAPK1/3 通路抑制剂的治疗提供证据，特别是在 ULK1 水平较低的癌症中。缩写：ATG：自噬相关； Baf A1：巴弗洛霉素A1； BTRC/β-TrCP：含有E3泛素蛋白连接酶的β-转导蛋白重复序列； CHX：放线菌酮； CM：条件培养基； FBXW7/FBW7：包含7个的F-box和WD重复结构域； MAPK1：丝裂原激活蛋白激酶1； MTDR：MitoTracker 深红色； mtROS：线粒体活性氧； microCT：微型计算机断层扫描； mtROS：线粒体活性氧； OCR：耗氧率； SQSTM1: 隔离体 1; ACP5/TRAP：酸性磷酸酶，抗酒石酸盐； ULK1：unc-51 样自噬激活激酶 1
ABSTRACT The function of mitophagy in cancer is controversial. ULK1 is critical for induction of macroautophagy/autophagy and has a more specific role in mitophagy in response to hypoxia. Here, we show that ULK1 deficiency induces an invasive phenotype of breast cancer cells under hypoxia and increases osteolytic bone metastasis. Mechanistically, ULK1 depletion attenuates mitophagy ability during hypoxia. As a result, the accumulation of damaged, ROS-generating mitochondria leads to activation of the NLRP3 inflammasome, which induces abnormal soluble cytokines secretion, then promotes the differentiation and maturation of osteoclasts, and ultimately results in bone metastasis. Notably, phosphorylation of ULK1 by MAPK1/ERK2-MAPK3/ERK1 kinase triggers its interaction with BTRC and subsequent K48-linked ubiquitination and proteasome degradation. Also, a clearly negative correlation between the expression levels of ULK1 and p-MAPK1/3 was observed in human breast cancer tissues. The MAP2K/MEK inhibitor trametinib is sufficient to restore mitophagy function via upregulation of ULK1, leading to inhibition of NLRP3 inflammasome activation, thereby reduces bone metastasis. These results indicate that ULK1 knockout-mediated mitophagy defect promotes breast cancer bone metastasis and provide evidence to explore MAP2K/MEK- MAPK1/3 pathway inhibitors for therapy, especially in cancers displaying low levels of ULK1. Abbreviations: ATG: autophagy-related; Baf A1: bafilomycin A1; BTRC/β-TrCP: beta-transducin repeat containing E3 ubiquitin protein ligase; CHX: cycloheximide; CM: conditioned media; FBXW7/FBW7: F-box and WD repeat domain containing 7; MAPK1: mitogen-activated protein kinase 1; MTDR: MitoTracker Deep Red; mtROS: mitochondrial reactive oxygen species; microCT: micro-computed tomography; mtROS: mitochondrial reactive oxygen species; OCR: oxygen consumption rate; SQSTM1: sequestosome 1; ACP5/TRAP: acid phosphatase, tartrate resistant; ULK1: unc-51 like autophagy activating kinase 1