MLN4924 inhibits hedgehog signaling pathway and activates autophagy to alleviate mouse laser-induced choroidal neovascularization lesion

Biomed Pharmacother. 2020 Oct;130:110654. doi: 10.1016/j.biopha.2020.110654. Epub 2020 Sep 1.ABSTRACTNeovascular age-related macular degeneration (nAMD), featured as choroidal neovascularization (CNV), can cause blindness in the elderly population. MLN4924, a highly selective small-molecule inhibitor of NEDD8 (neuronal precursor cell-expressed developmentally down-regulated protein 8)-activating enzyme (NAE), inhibits the proliferation, angiogenesis and inflammation of multiple cancers via up-regulating hedgehog pathway-regulated autophagy. MLN4924 intraperitoneal injection mitigated the leakage, area and volume of mouse laser-induced CNV lesion. Additionally, compared to CNV 7 d group, MLN4924 treated mouse retina-retinal pigment epithelium (RPE)-choroid complex showed decreased expression of hedgehog pathway-associated molecules patched 1 (PTCH1), smoothened (SMO), GLI family zinc finger 1 (GLI1) and GLI family zinc finger 2 (GLI2) with increased expression of autophagy-associated molecules sequestosome 1 (p62) and LC microtubule-associated protein 1 light chain 3 (LC3). Meanwhile, human choroidal endothelial cells (HCECs) exposed to hypoxia condition also showed decreased expression of hedgehog pathway-associated molecules and increased expression of autophagy-associated molecules. Compared to hypoxia + MLN4924 group, SMO agonist SAG up-regulated hedgehog pathway and down-regulated autophagy, whereas autophagy inhibitor PIK-III inhibited autophagy with no effect on hedgeho...
Source: Biomedicine and pharmacotherapy = Biomedecine and pharmacotherapie - Category: Drugs & Pharmacology Authors: Source Type: research