HMGB3 promotes PARP inhibitor resistance through interacting with PARP1 in ovarian cancer.
Animals
Antineoplastic Agents
/ pharmacology
Carcinoma, Ovarian Epithelial
/ drug therapy
Cell Line, Tumor
Drug Resistance, Neoplasm
/ genetics
Female
Humans
Mice
Ovarian Neoplasms
/ drug therapy
Phthalazines
/ pharmacology
Poly (ADP-Ribose) Polymerase-1
/ genetics
Poly(ADP-ribose) Polymerase Inhibitors
/ pharmacology
Poly(ADP-ribose) Polymerases
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
24 03 2022
24 03 2022
Historique:
received:
16
08
2021
accepted:
17
02
2022
revised:
11
02
2022
entrez:
25
3
2022
pubmed:
26
3
2022
medline:
15
4
2022
Statut:
epublish
Résumé
Poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) resistance remains a therapeutic challenge in ovarian cancer. High-mobility group box 3 (HMGB3) plays significant roles in the development of drug resistance of many cancers. However, the function of HMGB3 in PARPi resistance is poorly understood. In the current study, we clarified that HMGB3 was aberrantly overexpressed in high-grade serous ovarian carcinoma (HGSOC) tissues, and high HMGB3 levels indicated shorter overall survival and drug resistance in HGSOC. The overexpression of HMGB3 increased the insensitivity of ovarian cancer to PARPi, whereas HMGB3 knockdown reduced PARPi resistance. Mechanistically, PARP1 was identified as a novel interaction partner of HMGB3, which could be blocked using olaparib and was enhanced upon DNA damage conditions. We further showed that loss of HMGB3 induced PARP1 trapping at DNA lesions and inhibited the PARylation activity of PARP1, resulting in an increased DNA damage response and cell apoptosis. The PARPi-resistant role of HMGB3 was also verified in a xenograft mouse model. In conclusion, HMGB3 promoted PARPi resistance via interacting with PARP1, and the targeted inhibition of HMGB3 might overcome PARPi resistance in ovarian cancer therapy.
Identifiants
pubmed: 35332131
doi: 10.1038/s41419-022-04670-7
pii: 10.1038/s41419-022-04670-7
pmc: PMC8948190
doi:
Substances chimiques
Antineoplastic Agents
0
Phthalazines
0
Poly(ADP-ribose) Polymerase Inhibitors
0
PARP1 protein, human
EC 2.4.2.30
Poly (ADP-Ribose) Polymerase-1
EC 2.4.2.30
Poly(ADP-ribose) Polymerases
EC 2.4.2.30
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
263Informations de copyright
© 2022. The Author(s).
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