Polyphyllin VII induces autophagy-dependent ferroptosis in human gastric cancer through targeting T-lymphokine-activated killer cell-originated protein kinase.
TOPK
ULK1
autophagy
ferroptosis
gastric cancer
polyphyllin VII
Journal
Phytotherapy research : PTR
ISSN: 1099-1573
Titre abrégé: Phytother Res
Pays: England
ID NLM: 8904486
Informations de publication
Date de publication:
Dec 2023
Dec 2023
Historique:
revised:
20
07
2023
received:
25
04
2023
accepted:
06
08
2023
pubmed:
27
8
2023
medline:
27
8
2023
entrez:
26
8
2023
Statut:
ppublish
Résumé
T-lymphokine-activated killer cell-originated protein kinase (TOPK) is a serine-threonine kinase that is overexpressed in gastric cancer (GC) and promotes tumor progression. Polyphyllin VII (PPVII), a pennogenin isolated from the rhizomes of Paris polyphylla, shows anticancer effects. Here, we explored the antitumor activity and mechanism of PPVII in GC. Ferroptosis was detected by transmission electron microscope, malondialdehyde, and iron determination assays. Autophagy and its upstream signaling pathway were detected by Western blot, and gene alterations. The binding of PPVII and TOPK was examined through microscale thermophoresis and drug affinity responsive target stability assays. An in vivo mouse model was performed to evaluate the therapeutic of PPVII. PPVII inhibits GC by inducing autophagy-mediated ferroptosis. PPVII promotes the degradation of ferritin heavy chain 1, which is responsible for autophagy-mediated ferroptosis. PPVII activates the Unc-51-like autophagy-activating kinase 1 (ULK1) upstream of autophagy. PPVII inhibits the activity of TOPK, thereby weakening the inhibition of downstream ULK1. PPVII stabilizes the dimer of the inactive form of TOPK by direct binding. PPVII inhibits tumor growth without causing obvious toxicity in vivo. Collectively, this study suggests that PPVII is a potential agent for the treatment of GC by targeting TOPK to activate autophagy-mediated ferroptosis.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
5803-5820Subventions
Organisme : National Natural Science Foundation of China
ID : 81802387
Organisme : National Natural Science Foundation of China
ID : 82072928
Organisme : Foundation of Hubei Provincial Department of Science and Technology
ID : 2023AFB851
Organisme : Foundation of Hubei Provincial Department of Science and Technology
ID : 2022CFB548
Organisme : Foundation of Hubei Provincial Department of Science and Technology
ID : 2021CFA009
Organisme : Advantages Discipline Group Project in Higher Education of Hubei Province
ID : 2023XKQT2
Organisme : Innovative Research Program for Graduates
ID : YC2022032
Organisme : Innovative Research Program for Graduates
ID : YC2022031
Organisme : Faculty Development Grants
ID : 2021QDJZR025
Organisme : Scientific and Technological Project of Shiyan City of Hubei Province
ID : 22Y20
Organisme : the Foundation of Health and Family planning Commission of Hubei Province
ID : WJ2023F079
Informations de copyright
© 2023 John Wiley & Sons Ltd.
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