Kushenol E inhibits autophagy and impairs lysosomal positioning via VCP/p97 inhibition.

In this study, we evaluated the autophagy-regulatory effects of kushenol E (KE), a bi-prenylated flavonoid isolated from Sophora flavescens and found that KE increased LC3B-II levels while inducing the formation of autophagic vacuoles and immature autophagosomes in HeLa and HCT116 cells. Transmission electron microscopy images revealed that KE treatment generates immature autophagosomes. Furthermore, KE inhibited autophagosome maturation as demonstrated by blocking the degradation of EGFP puncta in HeLa cells stably expressing EGFP-mRFP-LC3B. It also reduced lysosomal activity and cathepsin maturation by disrupting lysosomal positioning, subsequently inducing apoptosis. Further, a combinatorial approach employing cellular thermal shift assays, revealed valosin-containing protein (VCP)/p97 as a potential target protein of KE; the knockdown and overexpression of VCP/p97 confirmed its involvement in regulating lysosomal positioning for autophagy maturation via direct interactions with KE. Thus, KE may possess autophagy-regulating properties mediated by binding to VCP/p97.
PMID: 32081789 [PubMed - as supplied by publisher]

Source: Biochemical Pharmacology - February 16, 2020 Category: Drugs & Pharmacology Authors: Kwon M, Jang M, Kim GH, Oh T, Ryoo IJ, Ryu HW, Oh SR, Kim BY, Jang JH, Ko SK, Ahn JS Tags: Biochem Pharmacol Source Type: research