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- Title
ATF3-induced activation of NF-κB pathway results in acquired PARP inhibitor resistance in pancreatic adenocarcinoma.
- Authors
Liu, Yang; Cao, Yizhi; Liu, Pengyi; Zhai, Shuyu; Liu, Yihao; Tang, Xiaomei; Lin, Jiayu; Shi, Minmin; Qi, Debin; Deng, Xiaxing; Zhu, Youwei; Wang, Weishen; Shen, Baiyong
- 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.
- Subjects
TRANSCRIPTION factors; POLY(ADP-ribose) polymerase; PANCREATIC cancer; OLAPARIB; ADENOCARCINOMA; IMMUNOPRECIPITATION; ADENOSINE diphosphate
- Publication
Cellular Oncology (2211-3428), 2024, Vol 47, Issue 3, p939
- ISSN
2211-3428
- Publication type
Article
- DOI
10.1007/s13402-023-00907-5