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

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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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Data availability

Data are available in a public, open-access datasets. ATAC-seq, ChIP-Seq and mRNA-seq data generated in this study are deposited at the National Omics Data Encyclopedia (NODE) with the accession code OEP004144 (https://www.biosino.org/node/).

References

  1. J.D. Mizrahi, R. Surana, J.W. Valle, R.T. Shroff, Pancreatic cancer. Lancet. 395(10242), 2008–2020 (2020)

    Article  CAS  PubMed  Google Scholar 

  2. J.P. Neoptolemos, J. Kleeff, P. Michl, E. Costello, W. Greenhalf, D.H. Palmer, Therapeutic developments in pancreatic cancer: current and future perspectives. Nat. Rev. Gastroenterol. Hepatol. 15(6), 333–348 (2018)

    Article  PubMed  Google Scholar 

  3. R.L. Siegel, K.D. Miller, H.E. Fuchs, A. Jemal, Cancer statistics, 2021. CA Cancer J. Clin. 71(1), 7–33 (2021)

    Article  PubMed  Google Scholar 

  4. W. Park, A. Chawla, E.M. O’Reilly, Pancreatic cancer: a review. JAMA. 326(9), 851–862 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. J. Mateo, C.J. Lord, V. Serra, A. Tutt, J. Balmaña, M. Castroviejo-Bermejo et al., A decade of clinical development of PARP inhibitors in perspective. Ann. Oncol. 30(9), 1437–1447 (2019)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. B. Kaufman, R. Shapira-Frommer, R.K. Schmutzler, M.W. Audeh, M. Friedlander, J. Balmaña et al., Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J. Clin. Oncol. 33(3), 244–250 (2015)

    Article  CAS  PubMed  Google Scholar 

  7. M. Robson, S.-A. Im, E. Senkus, B. Xu, S.M. Domchek, N. Masuda et al., Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N. Engl. J. Med. 377(6), 523–533 (2017)

    Article  CAS  PubMed  Google Scholar 

  8. K. Moore, N. Colombo, G. Scambia, B.-G. Kim, A. Oaknin, M. Friedlander et al., Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N. Engl. J. Med. 379(26), 2495–2505 (2018)

    Article  CAS  PubMed  Google Scholar 

  9. T. Golan, P. Hammel, M. Reni, E. Van Cutsem, T. Macarulla, M.J. Hall et al., Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N. Engl. J. Med. 381(4), 317–327 (2019)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. H. Li, Z.Y. Liu, N. Wu, Y.C. Chen, Q. Cheng, J. Wang, PARP inhibitor resistance: the underlying mechanisms and clinical implications. Mol. Cancer 19(1), 107 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. M.R. Thompson, D. Xu, B.R.G. Williams, ATF3 transcription factor and its emerging roles in immunity and cancer. J. Mol. Med. (Berl) 87(11), 1053–1060 (2009)

    Article  CAS  PubMed  Google Scholar 

  12. H. Zhou, N. Li, Y. Yuan, Y.-G. Jin, H. Guo, W. Deng et al., Activating transcription factor 3 in cardiovascular diseases: a potential therapeutic target. Basic Res. Cardiol. 113(5), 37 (2018)

    Article  PubMed  Google Scholar 

  13. H.-C. Ku, C.-F. Cheng, Master regulator activating transcription factor 3 (ATF3) in metabolic homeostasis and cancer. Front. Endocrinol. (Lausanne). 11, 556 (2020)

    Article  PubMed  PubMed Central  Google Scholar 

  14. E.J. Zmuda, L. Qi, M.X. Zhu, R.G. Mirmira, M.R. Montminy, T. Hai, The roles of ATF3, an adaptive-response gene, in high-fat-diet-induced diabetes and pancreatic beta-cell dysfunction. Mol. Endocrinol. 24(7), 1423–1433 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. N. Azizi, J. Toma, M. Martin, M.F. Khalid, F. Mousavi, P.W. Win et al., Loss of activating transcription factor 3 prevents KRAS-mediated pancreatic cancer. Oncogene 40(17), 3118–3135 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. J. Kuroda, M. Yamamoto, H. Nagoshi, T. Kobayashi, N. Sasaki, Y. Shimura, et al., Targeting activating transcription factor 3 by Galectin-9 induces apoptosis and overcomes various types of treatment resistance in chronic myelogenous leukemia. Mol. Cancer Res. 8(7), 994–1001 (2010)

  17. S. Borgoni, E. Sofyalı, M. Soleimani, H. Wilhelm, K. Müller-Decker, R. Will, et al., Time-resolved profiling reveals ATF3 as a novel mediator of endocrine resistance in breast cancer. Cancers. 12(10) (2020)

  18. S.L. Edwards, R. Brough, C.J. Lord, R. Natrajan, R. Vatcheva, D.A. Levine et al., Resistance to therapy caused by intragenic deletion in BRCA2. Nature 451(7182), 1111–1115 (2008)

    Article  CAS  PubMed  Google Scholar 

  19. N. Guo, M.Z. Li, L.M. Wang, H.D. Chen, S.S. Song, Z.H. Miao et al., Repeated treatments of Capan-1 cells with PARP1 and Chk1 inhibitors promote drug resistance, migration and invasion. Cancer Biol. Ther. 23(1), 69–82 (2022)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. A. Wicovsky, F. Henkler, S. Salzmann, P. Scheurich, C. Kneitz, H. Wajant, Tumor necrosis factor receptor-associated factor-1 enhances proinflammatory TNF receptor-2 signaling and modifies TNFR1–TNFR2 cooperation. Oncogene 28(15), 1769–1781 (2009)

    Article  CAS  PubMed  Google Scholar 

  21. M.-Q. Du, MALT lymphoma: a paradigm of NF-κB dysregulation. Semin. Cancer Biol. 39, 49–60 (2016)

    Article  PubMed  Google Scholar 

  22. S.F. Johnson, C. Cruz, A.K. Greifenberg, S. Dust, D.G. Stover, D. Chi et al., CDK12 inhibition reverses de novo and acquired PARP inhibitor resistance in BRCA wild-type and mutated models of triple-negative breast cancer. Cell Rep. 17(9), 2367–2381 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. O. Kondrashova, M. Topp, K. Nesic, E. Lieschke, G.-Y. Ho, M.I. Harrell et al., Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma. Nat. Commun. 9(1), 3970 (2018)

    Article  PubMed  PubMed Central  Google Scholar 

  24. S. Bandyopadhyay, Y. Wang, R. Zhan, S.K. Pai, M. Watabe, M. Iiizumi et al., The tumor metastasis suppressor gene Drg-1 down-regulates the expression of activating transcription factor 3 in prostate cancer. Can. Res. 66(24), 11983–11990 (2006)

    Article  CAS  Google Scholar 

  25. S. Kwok, S.R. Rittling, N.C. Partridge, C.S. Benson, M. Thiyagaraj, N. Srinivasan et al., Transforming growth factor-β1 regulation of ATF-3 and identification of ATF-3 target genes in breast cancer cells. J. Cell. Biochem. 108(2), 408–414 (2009)

    Article  CAS  PubMed  Google Scholar 

  26. Y.S. Chang, S.P. Jalgaonkar, J.D. Middleton, T. Hai, Stress-inducible gene Atf3 in the noncancer host cells contributes to chemotherapy-exacerbated breast cancer metastasis. Proc. Natl. Acad. Sci. 114(34), E7159–E7168 (2017)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. W. Zhao, M. Sun, S. Li, Z. Chen, D. Geng, Transcription factor ATF3 mediates the radioresistance of breast cancer. J. Cell. Mol. Med. 22(10), 4664–4675 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. D. Fu, C. Wang, L. Yu, R. Yu, Induction of ferroptosis by ATF3 elevation alleviates cisplatin resistance in gastric cancer by restraining Nrf2/Keap1/xCT signaling. Cell. Mol. Biol. Lett. 26(1), 26 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. A.C. Chüeh, J.W.T. Tse, M. Dickinson, P. Ioannidis, L. Jenkins, L. Togel et al., ATF3 repression of BCL-X determines apoptotic sensitivity to HDAC inhibitors across tumor types. Clin. Cancer Res. 23(18), 5573–5584 (2017)

    Article  PubMed  PubMed Central  Google Scholar 

  30. Y.H. Jan, H.Y. Tsai, C.J. Yang, M.S. Huang, Y.F. Yang, T.C. Lai et al., Adenylate kinase-4 is a marker of poor clinical outcomes that promotes metastasis of lung cancer by downregulating the transcription factor ATF3. Can. Res. 72(19), 5119–5129 (2012)

    Article  CAS  Google Scholar 

  31. J.-H. Zhu, Q.-L. Yan, J.-W. Wang, Y. Chen, Q.-H. Ye, Z.-J. Wang et al., The key genes for perineural invasion in pancreatic ductal adenocarcinoma identified with Monte-Carlo feature selection method. Front. Genet. 11, 554502 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Z. Zeng, F.Y. Xu, H. Zheng, P. Cheng, Q.Y. Chen, Z. Ye et al., LncRNA-MTA2TR functions as a promoter in pancreatic cancer via driving deacetylation-dependent accumulation of HIF-1α. Theranostics. 9(18), 5298–5314 (2019)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. M. Rohini, A. Haritha Menon, N. Selvamurugan, Role of activating transcription factor 3 and its interacting proteins under physiological and pathological conditions. Int. J. Biol. Macromol. 120, 310–317 (2018)

    Article  CAS  PubMed  Google Scholar 

  34. Y. Liang, Y. Jiang, X. Jin, P. Chen, Y. Heng, L. Cai et al., Neddylation inhibition activates the protective autophagy through NF-κB-catalase-ATF3 Axis in human esophageal cancer cells. Cell Commun. Signal 18(1), 72 (2020)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. M. Rohini, B. Arumugam, M. Vairamani, N. Selvamurugan, Stimulation of ATF3 interaction with Smad4 via TGF-β1 for matrix metalloproteinase 13 gene activation in human breast cancer cells. Int. J. Biol. Macromol. 134, 954–961 (2019)

    Article  CAS  PubMed  Google Scholar 

  36. K. Tamura, B. Hua, S. Adachi, I. Guney, J. Kawauchi, M. Morioka et al., Stress response gene ATF3 is a target of c-myc in serum-induced cell proliferation. EMBO J. 24(14), 2590–2601 (2005)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. M. Hamdi, H.E. Popeijus, F. Carlotti, J.M. Janssen, C. van der Burgt, P. Cornelissen-Steijger et al., ATF3 and Fra1 have opposite functions in JNK- and ERK-dependent DNA damage responses. DNA Repair 7(3), 487–496 (2008)

    Article  CAS  PubMed  Google Scholar 

  38. A. Oeckinghaus, M.S. Hayden, S. Ghosh, Crosstalk in NF-κB signaling pathways. Nat. Immunol. 12(8), 695–708 (2011)

    Article  CAS  PubMed  Google Scholar 

  39. H. Khan, H. Ullah, P.C.M.F. Castilho, A.S. Gomila, G. D’Onofrio, R. Filosa et al., Targeting NF-κB signaling pathway in cancer by dietary polyphenols. Crit. Rev. Food Sci. Nutr. 60(16), 2790–2800 (2020)

    Article  CAS  PubMed  Google Scholar 

  40. J. Ding, H. Li, Y. Liu, Y. Xie, J. Yu, H. Sun et al., OXCT1 enhances gemcitabine resistance through NF-κB pathway in pancreatic ductal adenocarcinoma. Front. Oncol. 11, 698302 (2021)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. J.W. Kwon, H.K. Kwon, H.J. Shin, Y.M. Choi, M.A. Anwar, S. Choi, Activating transcription factor 3 represses inflammatory responses by binding to the p65 subunit of NF-κB. Sci. Rep. 5, 14470 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. M. Gilchrist, V. Thorsson, B. Li, A.G. Rust, M. Korb, K. Kennedy et al., Systems biology approaches identify ATF3 as a negative regulator of Toll-like receptor 4. Nature 441(7090), 173–178 (2006)

    Article  CAS  PubMed  Google Scholar 

  43. F. Yan, Y. Wu, H. Liu, Y. Wu, H. Shen, W. Li, ATF3 is positively involved in particulate matter-induced airway inflammation in vitro and in vivo. Toxicol. Lett. 287, 113–121 (2018)

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Prof. Zehong Miao from the Division of Anti-Tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences for Olaparib-resistance Capan-1 cell line as a kindly gift to us.

Funding

This study was supported by grants from the National Natural Science Foundation of China (Nos.82073326), the Shanghai Sailing Program (No.22YF1426200), the Jiaotong University Medical-Engineering Cross Fund (No. YG2022QN007), the Shenkang center city hospital emerging frontier technology joint research project (No. SHDC12020121), and the Guangci Clinical Technology Sailing Project (No. YW20210033).

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Author notes

  1. Yang Liu, Yizhi Cao, and Pengyi Liu contributed equally to this work.

Authors and Affiliations

  1. Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China

    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

  2. Research Institute of Pancreatic Diseases, Shanghai Key Laboratory of Translational Research for Pancreatic Neoplasms, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China

    Yang Liu, Yizhi Cao, Pengyi Liu, Shuyu Zhai, Yihao Liu, Xiaomei Tang, Jiayu Lin, Minmin Shi, Xiaxing Deng, Youwei Zhu, Weishen Wang & Baiyong Shen

  3. State Key Laboratory of Oncogenes and Related Genes, Institute of Translational Medicine, Shanghai Jiaotong University, Shanghai, People’s Republic of China

    Yang Liu, Yizhi Cao, Pengyi Liu, Shuyu Zhai, Yihao Liu, Xiaomei Tang, Jiayu Lin, Minmin Shi, Xiaxing Deng, Youwei Zhu, Weishen Wang & Baiyong Shen

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  1. Yang Liu
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Contributions

Study concept and design, Liu Y, Cao Y, Wang W, Shen B; acquisition of data, Liu Y, Liu P, Zhai S, Lin J, Tang X, Shi M, ; analysis and interpretation of data, Liu Y, Cao Y, Liu Y; drafting of the manuscript, Liu Y, Cao Y; critical revision of the manuscript for important intellectual content, Shen B, Wang W; statistical analysis, Liu Y, Qi D; obtained funding, Shen B, Wang W, Zhu Y, Deng X; administrative, technical, or material support, Shen B, Wang W, Zhu Y; study supervision, Shen B, Wang W, Zhu Y. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Youwei Zhu, Weishen Wang or Baiyong Shen.

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Ethical approval

All animal experiments were approved by the Animal Ethics Committee of Shanghai Jiao Tong University (License number: SYXK Shanghai 2018–0027).

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The authors declare no competing interests.

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Liu, Y., Cao, Y., Liu, P. et al. ATF3-induced activation of NF-κB pathway results in acquired PARP inhibitor resistance in pancreatic adenocarcinoma. Cell Oncol. (2023). https://doi.org/10.1007/s13402-023-00907-5

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