LCK facilitates DNA damage repair by stabilizing RAD51 and BRCA1 in the nucleus of chemoresistant ovarian cancer.
Animals
Female
Humans
Mice
BRCA1 Protein
/ genetics
Carcinoma, Endometrioid
/ drug therapy
Carcinoma, Ovarian Epithelial
/ drug therapy
Cell Line, Tumor
DNA Damage
DNA Repair
Homologous Recombination
Ovarian Neoplasms
/ drug therapy
Poly(ADP-ribose) Polymerase Inhibitors
/ pharmacology
Rad51 Recombinase
/ genetics
Journal
Journal of ovarian research
ISSN: 1757-2215
Titre abrégé: J Ovarian Res
Pays: England
ID NLM: 101474849
Informations de publication
Date de publication:
27 Jun 2023
27 Jun 2023
Historique:
received:
24
01
2023
accepted:
24
05
2023
medline:
29
6
2023
pubmed:
28
6
2023
entrez:
27
6
2023
Statut:
epublish
Résumé
Poly-ADP Ribose Polymerase (PARP) targeted therapy is clinically approved for the treatment of homologous recombination (HR) repair deficient tumors. The remarkable success of this therapy in the treatment of HR repair deficient cancers has not translated to HR-proficient cancers. Our studies identify the novel role of non-receptor lymphocyte-specific protein tyrosine kinase (LCK) in the regulation of HR repair in endometrioid epithelial ovarian cancer (eEOC) model. We show that DNA damage leads to direct interaction of LCK with the HR repair proteins RAD51 and BRCA1 in a kinase dependent manner RAD51 and BRCA1 stabilization. LCK expression is induced and activated in the nucleus in response to DNA damage insult. Disruption of LCK expression attenuates RAD51, BRCA1, and BRCA2 protein expression by hampering there stability and results in inhibition of HR-mediated DNA repair including suppression of RAD51 foci formation, and augmentation of γH2AX foci formation. In contrast LCK overexpression leads to increased RAD51 and BRCA1 expression with a concomitant increase in HR DNA damage repair. Importantly, attenuation of LCK sensitizes HR-proficient eEOC cells to PARP inhibitor in cells and pre-clinical mouse studies. Collectively, our findings identify a novel therapeutic strategy to expand the utility of PARP targeted therapy in HR proficient ovarian cancer.
Identifiants
pubmed: 37370140
doi: 10.1186/s13048-023-01194-2
pii: 10.1186/s13048-023-01194-2
pmc: PMC10294509
doi:
Substances chimiques
BRCA1 Protein
0
BRCA1 protein, human
0
Poly(ADP-ribose) Polymerase Inhibitors
0
RAD51 protein, human
EC 2.7.7.-
Rad51 Recombinase
EC 2.7.7.-
LCK protein, human
EC 2.7.10.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
122Informations de copyright
© 2023. The Author(s).
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