ATF3-induced activation of NF-κB pathway results in acquired PARP inhibitor resistance in pancreatic adenocarcinoma

IF 6.6 2区 医学 Q1 Medicine Cellular Oncology Pub Date : 2023-12-15 DOI:10.1007/s13402-023-00907-5
Yang Liu, Yizhi Cao, Pengyi Liu, Shuyu Zhai, Yihao Liu, Xiaomei Tang, Jiayu Lin, Minmin Shi, Debin Qi, Xiaxing Deng, Youwei Zhu, Weishen Wang, Baiyong Shen
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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.

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ATF3 诱导的 NF-κB 通路激活导致胰腺腺癌对 PARP 抑制剂产生获得性耐药性
目的奥拉帕利是一种聚腺苷二磷酸核糖聚合酶(PARP)抑制剂,已被证明对BRCA1/2基因突变的胰腺癌患者有抗癌作用。方法在这项研究中,使用转座酶可及染色质测序法(ATAC-seq)和mRNA-seq评估了亲代胰腺癌细胞系和奥拉帕尼耐药胰腺癌细胞系的染色质可及性和差异表达转录本。结果根据通路富集分析,奥拉帕尼耐药细胞中的差异表达基因明显富集在 NF-κB 信号通路中。通过ATAC-seq,我们发现了奥拉帕尼耐药细胞中具有较高可及性的染色质区域,并预测了一系列重要的转录因子。其中,激活转录因子3(ATF3)明显高表达。结论体外和体内实验表明,ATF3可通过NF-κB信号通路增强奥拉帕尼耐药性,这表明ATF3可作为胰腺癌患者奥拉帕尼敏感性和预后指标。
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来源期刊
Cellular Oncology
Cellular Oncology Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
10.40
自引率
1.50%
发文量
0
审稿时长
16 weeks
期刊介绍: The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.
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