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.