Inhibiting Importin 4-mediated nuclear import of CEBPD enhances chemosensitivity by repression of PRKDC-driven DNA damage repair in cervical cancer.
Active Transport, Cell Nucleus
/ genetics
Animals
Antineoplastic Agents
/ pharmacology
CCAAT-Enhancer-Binding Protein-delta
/ genetics
Cell Line, Tumor
Chromones
/ pharmacology
Cisplatin
/ pharmacology
DNA Damage
DNA Repair
/ drug effects
DNA-Activated Protein Kinase
/ antagonists & inhibitors
Drug Resistance, Neoplasm
/ genetics
Female
Gene Expression Regulation, Neoplastic
HeLa Cells
Humans
Membrane Transport Proteins
/ genetics
Mice, Nude
Morpholines
/ pharmacology
RNA Interference
Uterine Cervical Neoplasms
/ genetics
Xenograft Model Antitumor Assays
/ methods
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
13
01
2020
accepted:
29
06
2020
revised:
10
06
2020
pubmed:
15
7
2020
medline:
1
12
2020
entrez:
15
7
2020
Statut:
ppublish
Résumé
Cervical cancer (CC) remains highest in the mortality of female reproductive system cancers, while cisplatin (CDDP) resistance is the one of main reasons for the lethality. Preceding evidence has supported that karyopherins are associated with chemoresistance. In this study, we simultaneously compared CDDP-incomplete responders with CDDP-complete responders of CC patients and CDDP-insensitive CC cell lines with CDDP-sensitive group. We finally identified that DNA-PKcs (PRKDC) was related to CDDP sensitivity after overlapping in CC sample tissues and CC cell lines. Further functional assay revealed that targeting PRKDC by shRNA and NU7026 (specific PRKDC inhibitor) could enhance CDDP sensitivity in vitro and in vivo, which was mediated by impairing DNA damage repair pathway in CC. Mechanistically, we found that PRKDC was transcriptionally upregulated by CCAAT/enhancer-binding protein delta (CEBPD), while intriguingly, CDDP treatment strengthened the transcriptional activity of CEBPD to PRKDC. We further disclosed that Importin 4 (IPO4) augmented the nuclear translocation of CEBPD through nuclear localization signals (NLS) to activate PRKDC-mediated DNA damage repair in response to CDDP. Moreover, we demonstrated that IPO4 and CEBPD knockdown improved CDDP-induced cytotoxicity in vitro and in vivo. Together, we shed the novel insight into the role of IPO4 in chemosensitivity and provide a clinical translational potential to enhance CC chemosensitivity since the IPO4-CEBPD-PRKDC axis is actionable via NU7026 (PRKDC inhibitor) or targeting IPO4 in combination with CDDP.
Identifiants
pubmed: 32661323
doi: 10.1038/s41388-020-1384-3
pii: 10.1038/s41388-020-1384-3
pmc: PMC7441007
doi:
Substances chimiques
2-(morpholin-4-yl)benzo(h)chromen-4-one
0
Antineoplastic Agents
0
CEBPD protein, human
0
Chromones
0
IPO4 protein, human
0
Membrane Transport Proteins
0
Morpholines
0
CCAAT-Enhancer-Binding Protein-delta
142662-43-9
DNA-Activated Protein Kinase
EC 2.7.11.1
PRKDC protein, human
EC 2.7.11.1
Cisplatin
Q20Q21Q62J
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5633-5648Références
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