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

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Title
Kushenol E inhibits autophagy and impairs lysosomal positioning via VCP/p97 inhibition
Author(s)
Mincheol Kwon; Mina Jang; Gun-Hee Kim; Taehoon Oh; In Ja RyooHyung Won RyuSei-Ryang OhBo Yeon KimJae-Hyuk JangSung-Kyun KoJong Seog Ahn
Bibliographic Citation
Biochemical Pharmacology, vol. 175, pp. 113861-113861
Publication Year
2020
Abstract
Autophagy plays a major role in cell survival and has therefore been exploited as an important strategy in cancer therapy. 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.
Keyword
AnticancerAutophagyKushenol E (KE)Lysosomal positioningVCP/p97
ISSN
0006-2952
Publisher
Elsevier
DOI
http://dx.doi.org/10.1016/j.bcp.2020.113861
Type
Article
Appears in Collections:
Ochang Branch Institute > Anticancer Agent Research Center > 1. Journal Articles
Ochang Branch Institute > Natural Medicine Research Center > 1. Journal Articles
Ochang Branch Institute > 1. Journal Articles
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