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Aloperine Suppresses Cancer Progression by Interacting with VPS4A to Inhibit Autophagosome‐lysosome Fusion in NSCLC.

Authors :
Guo, Weina
Zhou, Haifeng
Wang, Jingbo
Lu, Junjie
Dong, Yalan
Kang, Zhenyu
Qiu, Xiaoyuan
Ouyang, Xiaohu
Chen, Qianyun
Li, Junyi
Cheng, Xiang
Du, Keye
Li, Mingyue
Lin, Zhihao
Jin, Min
Zhang, Lei
Sarapultsev, Alexey
Shi, Kuangyu
Li, Fangfei
Zhang, Ge
Source :
Advanced Science. 8/21/2024, Vol. 11 Issue 31, p1-21. 21p.
Publication Year :
2024

Abstract

Aloperine (ALO), a quinolizidine‐type alkaloid isolated from a natural Chinese herb, has shown promising antitumor effects. Nevertheless, its common mechanism of action and specific target remain elusive. Here, it is demonstrated that ALO inhibits the proliferation and migration of non‐small cell lung cancer cell lines in vitro and the tumor development in several mouse tumor models in vivo. Mechanistically, ALO inhibits the fusion of autophagosomes with lysosomes and the autophagic flux, leading to the accumulation of sequestosome‐1 (SQSTM1) and production of reactive oxygen species (ROS), thereby inducing tumor cell apoptosis and preventing tumor growth. Knockdown of SQSTM1 in cells inhibits ROS production and reverses ALO‐induced cell apoptosis. Furthermore, VPS4A is identified as a direct target of ALO, and the amino acids F153 and D263 of VPS4A are confirmed as the binding sites for ALO. Knockout of VPS4A in H1299 cells demonstrates a similar biological effect as ALO treatment. Additionally, ALO enhances the efficacy of the anti‐PD‐L1/TGF‐β bispecific antibody in inhibiting LLC‐derived subcutaneous tumor models. Thus, ALO is first identified as a novel late‐stage autophagy inhibitor that triggers tumor cell death by targeting VPS4A. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
21983844
Volume :
11
Issue :
31
Database :
Academic Search Index
Journal :
Advanced Science
Publication Type :
Academic Journal
Accession number :
179140746
Full Text :
https://doi.org/10.1002/advs.202308307