Aloperine Suppresses Cancer Progression by Interacting with VPS4A to Inhibit Autophagosome-lysosome Fusion in NSCLC.
Animals
Mice
Carcinoma, Non-Small-Cell Lung
/ metabolism
Humans
Autophagosomes
/ metabolism
Lung Neoplasms
/ metabolism
Lysosomes
/ metabolism
Cell Line, Tumor
Quinolizidines
/ pharmacology
Disease Models, Animal
Vesicular Transport Proteins
/ metabolism
Disease Progression
Cell Proliferation
/ drug effects
Autophagy
/ drug effects
Apoptosis
/ drug effects
VPS4A
apoptosis
autophagy inhibition
non‐small cell lung cancer
sequestosome‐1
Journal
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
ISSN: 2198-3844
Titre abrégé: Adv Sci (Weinh)
Pays: Germany
ID NLM: 101664569
Informations de publication
Date de publication:
Aug 2024
Aug 2024
Historique:
revised:
12
05
2024
received:
01
11
2023
medline:
21
8
2024
pubmed:
21
8
2024
entrez:
21
8
2024
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 39166458
doi: 10.1002/advs.202308307
doi:
Substances chimiques
Quinolizidines
0
aloperine
56293-29-9
Vesicular Transport Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e2308307Subventions
Organisme : National Natural Science Foundation of China
ID : 81974249
Organisme : National Natural Science Foundation of China
ID : 82274317
Organisme : National Natural Science Foundation of China
ID : 82070136
Organisme : National Natural Science Foundation of China
ID : 82073370
Organisme : National Natural Science Foundation of China
ID : 82161138017
Organisme : Hubei Provincial Natural Science Foundation of Traditional Chinese Medicine
ID : ZY2023M020
Organisme : The Foundation of Hubei Key Laboratory of Biological Targeted Therapy
ID : 2023swbx021
Informations de copyright
© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.
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