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ATF3-induced activation of NF-κB pathway results in acquired PARP inhibitor resistance in pancreatic adenocarcinoma.
- Source :
-
Cellular Oncology (2211-3428) . Jun2024, Vol. 47 Issue 3, p939-950. 12p. - Publication Year :
- 2024
-
Abstract
- Purpose: Olaparib, an inhibitor of poly-(adenosine diphosphate-ribose) polymerase (PARP), has been shown to have anticancer benefits in patients with pancreatic cancer who have a germline mutation in BRCA1/2. However, resistance acquired on long-term exposure to olaparib significantly impedes clinical efficacy. Methods: In this study, the chromatin accessibility and differentially expressed transcripts of parental and olaparib-resistant pancreatic cancer cell lines were assessed using the Assay for Transposase Accessible Chromatin with sequencing (ATAC-seq) and mRNA-seq. Detection of downstream genes regulated by transcription factors using ChIP (Chromatin immunoprecipitation assay). Results: According to pathway enrichment analysis, differentially expressed genes in olaparib-resistant cells were remarkably enriched in the NF-κB signaling pathway. With ATAC-seq, we identified chromatin regions with higher accessibility in olaparib-resistant cells and predicted a series of important transcription factors. Among them, activating transcription factor 3 (ATF3) was significantly highly expressed. Functional experiments verified that inhibition of ATF3 suppressed the NF-κB pathway significantly and restored olaparib sensitivity in olaparib-resistant cells. Conclusion: Experiments in vitro and in vivo indicate ATF3 enhances olaparib resistance through the NF-κB signaling pathway, suggesting that ATF3 could be employed as an olaparib sensitivity and prognostic indicator in patients with pancreatic cancer. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 22113428
- Volume :
- 47
- Issue :
- 3
- Database :
- Academic Search Index
- Journal :
- Cellular Oncology (2211-3428)
- Publication Type :
- Academic Journal
- Accession number :
- 178230707
- Full Text :
- https://doi.org/10.1007/s13402-023-00907-5