Kaempferol inhibits non-homologous end joining repair via regulating Ku80 stability in glioma cancer.
DNA repair
Glioma
Kaempferol
Ku80
Non-homologous end joining
Journal
Phytomedicine : international journal of phytotherapy and phytopharmacology
ISSN: 1618-095X
Titre abrégé: Phytomedicine
Pays: Germany
ID NLM: 9438794
Informations de publication
Date de publication:
25 Jul 2023
25 Jul 2023
Historique:
received:
21
01
2023
revised:
29
04
2023
accepted:
10
05
2023
medline:
12
6
2023
pubmed:
22
5
2023
entrez:
21
5
2023
Statut:
ppublish
Résumé
Targeting DNA damage response and DNA repair proficiency of cancers is an important anticancer strategy. Kaempferol (Kae), a natural flavonoid, displays potent antitumor properties in some cancers. However, the precise underlying mechanism of Kae regulates DNA repair system are poorly understood. We aim to evaluate the efficacy of Kae in the treatment of human glioma as well as the molecular mechanism regarding DNA repair. Effects of Kae on glioma cells were detected using CCK-8 and EdU labeling assays. The molecular mechanism of Kae on glioma was determined using RNAseq. The inhibition effects of Kae on DNA repair were verified using Immunoprecipitation, immunofluorescence, and pimEJ5-GFP report assays. For in vivo study, orthotopic xenograft models were established and treated with Kae or vehicle. Glioma development was monitored by bioluminescence imaging, Magnetic Resonance Imaging (MRI), and brain sections Hematoxylin/Eosin (HE) staining. Immunohistochemical (IHC) analysis was used to detect expression of Ku80, Ki67 and γH2AX in engrafted glioma tissue. We found that Kae remarkably inhibits viability of glioma cells and decreases its proliferation. Mechanistically, Kae regulates multiple functional pathways associated with cancer, including non-homologous end joining (NHEJ) repair. Further studies revealed that Kae inhibits release of Ku80 from the double-strand breaks (DSBs) sites via reducing ubiquitylation and degradation of Ku80. Therefore, Kae significantly suppresses NHEJ repair and induces accumulation of DSBs in glioma cells. Moreover, Kae displays a dramatic inhibition effects on glioma growth in an orthotopic transplantation model. These data demonstrate that Kae can induce deubiquitination of Ku80, suppress NHEJ repair and inhibit glioma growth. Our findings indicate that inhibiting release of Ku80 from the DSBs by Kae may be a potential effective approach for glioma treatment.
Sections du résumé
BACKGROUND
BACKGROUND
Targeting DNA damage response and DNA repair proficiency of cancers is an important anticancer strategy. Kaempferol (Kae), a natural flavonoid, displays potent antitumor properties in some cancers. However, the precise underlying mechanism of Kae regulates DNA repair system are poorly understood.
PURPOSE
OBJECTIVE
We aim to evaluate the efficacy of Kae in the treatment of human glioma as well as the molecular mechanism regarding DNA repair.
STUDY DESIGN
METHODS
Effects of Kae on glioma cells were detected using CCK-8 and EdU labeling assays. The molecular mechanism of Kae on glioma was determined using RNAseq. The inhibition effects of Kae on DNA repair were verified using Immunoprecipitation, immunofluorescence, and pimEJ5-GFP report assays. For in vivo study, orthotopic xenograft models were established and treated with Kae or vehicle. Glioma development was monitored by bioluminescence imaging, Magnetic Resonance Imaging (MRI), and brain sections Hematoxylin/Eosin (HE) staining. Immunohistochemical (IHC) analysis was used to detect expression of Ku80, Ki67 and γH2AX in engrafted glioma tissue.
RESULTS
RESULTS
We found that Kae remarkably inhibits viability of glioma cells and decreases its proliferation. Mechanistically, Kae regulates multiple functional pathways associated with cancer, including non-homologous end joining (NHEJ) repair. Further studies revealed that Kae inhibits release of Ku80 from the double-strand breaks (DSBs) sites via reducing ubiquitylation and degradation of Ku80. Therefore, Kae significantly suppresses NHEJ repair and induces accumulation of DSBs in glioma cells. Moreover, Kae displays a dramatic inhibition effects on glioma growth in an orthotopic transplantation model. These data demonstrate that Kae can induce deubiquitination of Ku80, suppress NHEJ repair and inhibit glioma growth.
CONCLUSION
CONCLUSIONS
Our findings indicate that inhibiting release of Ku80 from the DSBs by Kae may be a potential effective approach for glioma treatment.
Identifiants
pubmed: 37210962
pii: S0944-7113(23)00237-4
doi: 10.1016/j.phymed.2023.154876
pii:
doi:
Substances chimiques
Ku Autoantigen
EC 4.2.99.-
Kaempferols
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
154876Informations de copyright
Copyright © 2023 Elsevier GmbH. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All data were generated in-house, and no paper mill was used. All authors agree to be accountable for all aspects of work ensuring integrity and accuracy.