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The antioxidant transcription factor Nrf2 modulates the stress response and phenotype of malignant as well as premalignant pancreatic ductal epithelial cells by inducing expression of the ATF3 splicing variant ΔZip2

Oncogene volume 38, pages 1461–1476 (2019)Cite this article

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) exhibits one of the worst survival rates of all cancers. While death rates show declining trends in the majority of cancers, PDAC registers rising rates. Based on the recently described crosstalk between TGF-β1 and Nrf2 in the PDAC development, the involvement of ATF3 and its splice variant ΔZip2 in TGF-β1- and Nrf2-driven pancreatic tumorigenesis was investigated. As demonstrated here, PDAC (Panc1, T3M4) cells or premalignant H6c7 pancreatic ductal epithelial cells differentially express ΔZip2- and ATF3, relating to stronger Nrf2 activity seen in Panc1 cells and TGF-ß1 activity in T3M4 or H6c7 cells, respectively. Treatment with the electrophile/oxidative stress inducer tBHQ or the cytostatic drug gemcitabine strongly elevated ΔZip2 expression in a Nrf2-dependent fashion. The differential expression of ATF3 and ΔZip2 in response to Nrf2 and TGF-ß1 relates to differential ATF3-gene promoter usage, giving rise of distinct splice variants. Nrf2-dependent ΔZip2 expression confers resistance against gemcitabine-induced apoptosis, only partially relating to interference with ATF3 and its proapoptotic activity, e.g., through CHOP-expression. In fact, ΔZip2 autonomously activates expression of cIAP anti-apoptotic proteins. Moreover, ΔZip2 favors and ATF3 suppresses growth and clonal expansion of PDAC cells, again partially independent of each other. Using a Panc1 tumor xenograft model in SCID-beige mice, the opposite activities of ATF3 and ΔZip2 on tumor-growth and chemoresistance were verified in vivo. Immunohistochemical analyses confirmed ΔZip2 and Nrf2 coexpression in cancerous and PanIN structures of human PDAC and chronic pancreatitis tissues, respectively, which to some extent was reciprocal to ATF3 expression. It is concluded that depending on selective ATF3-gene promoter usage by Nrf2, the ΔZip2 expression is induced in response to electrophile/oxidative (here through tBHQ) and xenobiotic (here through gemcitabine) stress, providing apoptosis protection and growth advantages to pancreatic ductal epithelial cells. This condition may substantially add to pancreatic carcinogenesis driven by chronic inflammation.

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References

  1. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.

    Article  PubMed  Google Scholar 

  2. Distler M, Aust D, Weitz J, Pilarsky C, Grützmann R. Precursor lesions for sporadic pancreatic cancer: PanIN, IPMN, and MCN. Biomed Res Int. 2014;2014:474905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. La Rosa S, Sessa F, Capella C. Acinar cell carcinoma of the pancreas: overview of clinicopathologic features and insights into the molecular pathology. Front Med. 2015;2:41

    Google Scholar 

  4. Reichert M, Blume K, Kleger A, Hartmann D, von Figura G. Developmental pathways direct pancreatic cancer initiation from its cellular origin. Stem Cells Int. 2016;2016:9298535.

    Article  PubMed  Google Scholar 

  5. Smit VT, Boot AJ, Smits AM, Fleuren GJ, Cornelisse CJ, Bos JL. KRAS codon 12 mutations occur very frequently in pancreatic adenocarcinomas. Nucleic Acids Res. 1988;16:7773–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kanda M, Matthaei H, Wu J, Hong SM, Yu J, Borges M, et al. Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology. 2012;142:730–3.

    Article  CAS  PubMed  Google Scholar 

  7. Löhr M, Schmidt C, Ringel J, Kluth M, Müller P, Nizze H, et al. Transforming growth factor-beta1 induces desmoplasia in an experimental model of human pancreatic carcinoma. Cancer Res. 2001;61:550–5.

    PubMed  Google Scholar 

  8. Bachem MG, Schünemann M, Ramadani M, Siech M, Beger H, Buck A, et al. Pancreatic carcinoma cells induce fibrosis by stimulating proliferation and matrix synthesis of stellate cells. Gastroenterology. 2005;128:907–21.

    Article  CAS  PubMed  Google Scholar 

  9. Pandol S, Edderkaoui M, Gukovsky I, Lugea A, Gukovskaya A. Desmoplasia of pancreatic ductal adenocarcinoma. Clin Gastroenterol Hepatol. 2009;7:S44–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Evans A, Costello E. The role of inflammatory cells in fostering pancreatic cancer cell growth and invasion. Front Physiol. 2012;3:270.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Sipos B, Frank S, Gress T, Hahn S, Klöppel G. Pancreatic intraepithelial neoplasia revisited and updated. Pancreatology. 2009;9:45–54.

    Article  CAS  PubMed  Google Scholar 

  12. Erkan M. The role of pancreatic stellate cells in pancreatic cancer. Pancreatology. 2013;13:106–9.

    Article  CAS  PubMed  Google Scholar 

  13. Disis ML. Immune regulation of cancer. J Clin Oncol. 2010;28:4531–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Farrow B, Evers BM. Inflammation and the development of pancreatic cancer. Surg Oncol. 2002;10:153–69.

    Article  PubMed  Google Scholar 

  15. Inman KS, Francis AA, Murray NR. Complex role for the immune system in initiation and progression of pancreatic cancer. World J Gastroenterol. 2014;20:11160–81.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Kang KW, Lee SJ, Kim SG. Molecular mechanism of nrf2 activation by oxidative stress. Antioxid Redox Signal. 2005;7:1664–73.

    Article  CAS  PubMed  Google Scholar 

  17. Kaspar JW, Niture SK, Jaiswal AK. Nrf2:INrf2 (Keap1) signaling in oxidative stress. Free Radic Biol Med. 2009;47:1304–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Osburn WO, Kensler TW. Nrf2 signaling: an adaptive response pathway for protection against environmental toxic insults. Mutat Res. 2008;659:31–9.

    Article  CAS  PubMed  Google Scholar 

  19. Sporn MB, Liby KT. NRF2 and cancer: the good, the bad and the importance of context. Nat Rev Cancer. 2012;12:564–71.

    Article  CAS  PubMed  Google Scholar 

  20. Ganan-Gomez I, Wei Y, Yang H, Boyano-Adanez MC, Garcia-Manero G. Oncogenic functions of the transcription factor Nrf2. Free Radic Biol Med. 2013;65:750–64.

    Article  CAS  PubMed  Google Scholar 

  21. Jaramillo MC, Zhang DD. The emerging role of the Nrf2-Keap1 signaling pathway in cancer. Genes Dev. 2013;27:2179–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Geismann C, Arlt A, Sebens S, Schäfer H. Cytoprotection gone astray: the role of Nrf2 in cancer. Oncol Target Ther. 2014;7:1497–518.

    Google Scholar 

  23. DeNicola GM, Karreth FA, Humpton TJ, Gopinathan A, Wei C, Frese K, et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature. 2011;475:106–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lister A, Nedjadi T, Kitteringham NR, Campbell F, Costello E, Lloyd B, et al. Nrf2 is overexpressed in pancreatic cancer: implications for cell proliferation and therapy. Mol Cancer. 2011;10:37 https://doi.org/10.1186/1476-4598-10-37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Arlt A, Sebens S, Krebs S, Geismann C, Grossmann M, Kruse ML, et al. Inhibition of the Nrf2 transcription factor by the alkaloid trigonelline renders pancreatic cancer cells more susceptible to apoptosis through decreased proteasomal gene expression and proteasome activity. Oncogene. 2013;32:4825–35.

    Article  CAS  PubMed  Google Scholar 

  26. Hayes AJ, Skouras C, Haugk B, Charnley RM. Keap1-Nrf2 signalling in pancreatic cancer. Int J Biochem Cell Biol. 2015;65:288–99.

    Article  CAS  PubMed  Google Scholar 

  27. Murakami S, Motohashi H. Roles of Nrf2 in cell proliferation and differentiation. Free Radic Biol Med. 2015;88:168–78.

    Article  CAS  PubMed  Google Scholar 

  28. Ren D, Villeneuve NF, Jiang T, Wu T, Lau A, Toppin HA, et al. Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism. Proc Natl Acad Sci USA. 2011;108:1433–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Arfmann-Knübel S, Struck B, Genrich G, Helm O, Sipos B, Sebens S, et al. The crosstalk between Nrf2 and TGF-β1 in the epithelial–mesenchymal transition of pancreatic duct epithelial cells. PLoS One. 2015. https://doi.org/10.1371/journal.pone.0132978.

  30. Mitsuishi Y, Taguchi K, Kawatani Y, Shibata T, Nukiwa T, Aburatani H, et al. Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell. 2012;22:66–79.

    Article  CAS  PubMed  Google Scholar 

  31. Hawkins KE, Joy S, Delhove JM, Kotiadis VN, Fernandez E, Fitzpatrick LM, et al. NRF2 orchestrates the metabolic shift during induced pluripotent stem cell reprogramming. Cell Rep. 2016;14:1883–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Taguchi K, Motohashi H, Yamamoto M. Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution. Genes Cells. 2011;16:123–40.

    Article  CAS  PubMed  Google Scholar 

  33. Yin X, Dewille JW, Hai T. A potential dichotomous role of ATF3, an adaptive-response gene, in cancer development. Oncogene. 2008;27:2118–27.

    Article  CAS  PubMed  Google Scholar 

  34. Thompson M, Xu D, Williams BRG. ATF3 transcription factor and its emerging roles in immunity and cancer. J Mol Med. 2009;11:1053–60.

    Article  Google Scholar 

  35. Liang G, Wolfgang CD, Chen BP, Chen TH, Hai T. ATF3 gene. Genomic organization, promoter, and regulation. J Biol Chem. 1996;271:1695–701.

    Article  CAS  PubMed  Google Scholar 

  36. Hai T, Wolfgang CD, Marsee DK, Allen AE, Sivaprasad U. ATF3 and stress responses. Gene Expr. 1999;7:321–35.

    CAS  PubMed  Google Scholar 

  37. Nilsson M, Ford J, Bohm S, Toftgård R. Characterization of a nuclear factor that binds juxtaposed with ATF3/Jun on a composite response element specifically mediating induced transcription in response to an epidermal growth factor/Ras/Raf signaling pathway. Cell Growth Differ. 1997;8:913–20.

    CAS  PubMed  Google Scholar 

  38. Brown SL, Sekhar KR, Rachakonda G, Sasi S, Freeman ML. Activating transcription factor 3 is a novel repressor of the nuclear factor erythroid-derived 2-related factor 2 (Nrf2)-regulated stress pathway. Cancer Res. 2008;68:364–8.

    Article  CAS  PubMed  Google Scholar 

  39. Buganim Y, Madar S, Rais Y, Pomeraniec L, Harel E, Solomon H, et al. Transcriptional activity of ATF3 in the stromal compartment of tumors promotes cancer progression. Carcinogenesis. 2011;32:1749–57.

    Article  CAS  PubMed  Google Scholar 

  40. Sato A, Nakama K, Watanabe H, Satake A, Yamamoto A, Omi T, et al. Role of activating transcription factor 3 protein ATF3 in necrosis and apoptosis induced by 5-fluoro-2′-deoxyuridine. FEBS J. 2014;281:1892–900.

    Article  CAS  PubMed  Google Scholar 

  41. Jiang X, Kim KJ, Ha T, Lee SH. Potential dual role of activating transcription factor 3 in colorectal cancer. Anticancer Res. 2016;36:509–16.

    CAS  PubMed  Google Scholar 

  42. Hashimoto Y, Zhang C, Kawauchi J, Imoto I, Adachi MT, Inazawa J, et al. An alternatively spliced isoform of transcriptional repressor ATF3 and its induction by stress stimuli. Nucleic Acids Res. 2002;30:2398–406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Chen BP, Liang G, Whelan J, Hai T. ATF3 and ATF3 delta Zip. Transcriptional repression versus activation by alternatively spliced isoforms. J Biol Chem. 1994;269:15819–26.

    CAS  PubMed  Google Scholar 

  44. Miyazaki K, Inoue S, Yamada K, Watanabe M, Liu Q, Watanabe T, et al. Differential usage of alternate promoters of the human stress response gene ATF3 in stress response and cancer cells. Nucleic Acids Res. 2009;37:1438–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hunt D, Raivich G, Anderson PN. Activating transcription factor 3 and the nervous system. Front Mol Neurosci. 2012;14:5–7.

    Google Scholar 

  46. Kim KH, Jeong JY, Surh YJ, Kim KW. Expression of stress-response ATF3 is mediated by Nrf2 in astrocytes. Nucleic Acids Res. 2010;38:48–59.

    Article  CAS  PubMed  Google Scholar 

  47. Jiang HY, Wek SA, McGrath BC, Lu D, Hai T, Harding HP, et al. Activating transcription factor 3 is integral to the eukaryotic initiation factor 2 kinase stress response. Mol Cell Biol. 2004;24:1365–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. O’Brien A, Barber JE, Reid S, Niknejad N, Dimitroulakos J. Enhancement of cisplatin cytotoxicity by disulfiram involves activating transcription factor 3. Anticancer Res. 2012;32:2679–88.

    PubMed  Google Scholar 

  49. Weng S, Zhou L, Deng Q, Wang J, Yu Y, Zhu J, et al. Niclosamide induced cell apoptosis via upregulation of ATF3 and activation of PERK in hepatocellular carcinoma cells. BMC Gastroenterol. 2016;16:25.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Genrich G, Kruppa M, Lenk L, Helm O, Broich A, Freitag-Wolf S, et al. The anti-oxidative transcription factor nuclear factor E2 related factor-2 (Nrf2) counteracts TGF-β1 mediated growth inhibition of pancreatic ductal epithelial cells −Nrf2 as determinant of pro-tumorigenic functions of TGF-β1. BMC Cancer. 2016;16:155.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Hua B, Tamamori-Adachi M, Luo Y, Tamura K, Morioka M, Fukuda M, et al. A splice variant of stress response gene ATF3 counteracts NF-kappaB-dependent anti-apoptosis through inhibiting recruitment of CREB-binding protein/p300 coactivator. J Biol Chem. 2006;281:1620–9.

    Article  CAS  PubMed  Google Scholar 

  52. Pan Y, Chen H, Siu F, Kilberg MS. Amino acid deprivation and endoplasmic reticulum stress induce expression of multiple activating transcription factor-3 mRNA species that, when overexpressed in HepG2 cells, modulate transcription by the human asparagine synthetase promoter. J Biol Chem. 2003;278:38402–12.

    Article  CAS  PubMed  Google Scholar 

  53. Dziunycz PJ, Lefort K, Wu X, Freiberger SN, Neu J, Djerbi N, et al. The oncogene ATF3 is potentiated by cyclosporine A and ultraviolet light A. J Invest Dermatol. 2014;134:1998–2004.

    Article  CAS  PubMed  Google Scholar 

  54. Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, et al. Diversification of transcriptional modulation: large scale identification and characterization of putative alternative promoters of human genes. Genome Res. 2006;16:55–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Esakky P, Hansen DA, Drury AM, Moley KH. Cigarette smoke-induced cell cycle arrest in spermatocytes [GC-2spd(ts)] is mediated through crosstalk between Ahr-Nrf2 pathway and MAPK signaling. J Mol Cell Biol. 2015;7:73–87.

    Article  PubMed  Google Scholar 

  56. Hiss DC, Gabriels GA. Implications of endoplasmic reticulum stress, the unfolded protein response and apoptosis for molecular cancer therapy. Part I: targeting p53, Mdm2, GADD153/CHOP, GRP78/BiP and heat shock proteins. Expert Opin Drug Discov. 2009;4:799–821.

    Article  CAS  PubMed  Google Scholar 

  57. Sano R, Reed JC. ER stress-induced cell death mechanisms. Biochim Biophys Acta. 2013;1833:3460–70.

    Article  CAS  PubMed  Google Scholar 

  58. Geismann C, Morscheck M, Koch D, Bergmann F, Ungefroren H, Arlt A, et al. Up-regulation of L1CAM in pancreatic duct cells is transforming growth factor beta1- and slug-dependent: role in malignant transformation of pancreatic cancer. Cancer Res. 2009;69:4517–26.

    Article  CAS  PubMed  Google Scholar 

  59. Yin X, Wolford CC, Chang YS, McConoughey SJ, Ramsey SA, Aderem A, et al. ATF3, an adaptive-response gene, enhances TGF-ß1 signaling and cancer-initiating cell features in breast cancer cells. J Cell Sci. 2010;123:3558–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Wang A, Arantes S, Yan L, Kiguchi K, McArthur MJ, Sahin A, et al. The transcription factor ATF3 acts as an oncogene in mouse mammary tumorigenesis. BMC Cancer. 2008;8:268.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ouyang H, Mou Lj, Luk C, Liu N, Karaskova J, Squire J, et al. Immortal human pancreatic duct epithelial cell lines with near normal genotype and phenotype. Am J Pathol. 2000;157:1623–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Sebens Müerköster S, Werbing V, Koch D, Sipos B, Ammerpohl O, Kalthoff H, et al. Role of myofibroblasts on innate chemoresistance in pancreatic carcinoma—epigenetic down-regulation of caspases. Int J Cancer. 2008;123:1751–60.

    Article  Google Scholar 

  63. Helm O, Mennrich R, Petrick D, Göbel L, Freitag-Wolf S, Roeder C, et al. Comparative characterization of stromal cells and ductal epithelium in chronic pancreatitis and pancreatic ductal adenocarcinoma. PLoS ONE. 2014;9:e94357 https://doi.org/10.1371/journal.pone.0094357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Bakin AV, Stourman NV, Sekhar KR, Rinehart C, Yan X, Meredith MJ, et al. Smad3-ATF3 signaling mediates TGF-beta suppression of genes encoding Phase II detoxifying proteins. Free Radic Biol Med. 2005;38:375–87.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank Maike Witt-Ramdohr, Iris Kosmol, and Dagmar Leisner (from the Institute of Experimental Cancer Research) as well as Sandra Krüger and Deniza Hajzeri (both from the Institute of Pathology) for excellent technical assistance. Special thanks also to Dr. Christian Röder (Biomaterial Bank of the Comprehensive Cancer Center Kiel) for supporting gene expression analysis on PDAC patient tissues and Dr. Claudia Geismann (Department of Internal Medicine) for assistance with mice experiments.

Funding

Financial support by the Medical Faculty of the CAU Kiel (to HS and OH) and the Cluster of Excellence “Inflammation at Interfaces” (to HS, AA, and SS) is greatly acknowledged.

Author contributions

MLK, LH, and FD conducted the experiments. CR and BS contributed to histochemistry experiments and data analysis. SS, AA, OH, and HS designed the study. OH and HS wrote the manuscript. All authors read and approved the contents of the manuscript and its publication.

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  1. Part of a doctoral thesis (MLK).

Authors and Affiliations

  1. Laboratory of Molecular Gastroenterology & Tumor Biology, Institute for Experimental Cancer Research, Christian-Albrechts-University & UKSH Campus Kiel, Bldg. 17, Arnold-Heller-Straße 3, 24105, Kiel, Germany

    My-Lan Kha, Lisa Hesse, Florian Deisinger & Heiner Schäfer

  2. Department of Pathology and Neuropathology, University Hospital Tübingen, Liebermeisterstr. 8, 72076, Tübingen, Germany

    Bence Sipos

  3. Institute of Pathology, Christian-Albrechts-University & UKSH Campus Kiel, Bldg. 14, Arnold-Heller-Straße 3, 24105, Kiel, Germany

    Christoph Röcken

  4. Biomaterial Bank of the Comprehensive Cancer Center Kiel, UKSH Campus Kiel, Bldg. 17, Arnold-Heller-Straße 3, 24105, Kiel, Germany

    Christoph Röcken & Susanne Sebens

  5. Laboratory of Gastrointestinal Signal Transduction, Department of Internal Medicine I, UKSH Campus Kiel, Bldg. 6, Arnold-Heller-Straße 3, 24105 Kiel, Germany

    Alexander Arlt

  6. Group Inflammatory Carcinogenesis, Institute for Experimental Cancer Research, Christian-Albrechts-University & UKSH Campus Kiel, Bldg. 17, Arnold-Heller-Straße 3, 24105, Kiel, Germany

    Susanne Sebens & Ole Helm

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Ethics committees (University Hospital Tübingen, reference: 470/210BO1; Medical Faculty of Kiel University, reference: D400/14; P2N_2018-035) approved the study. Written informed consent was obtained from all patients.

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Kha, ML., Hesse, L., Deisinger, F. et al. The antioxidant transcription factor Nrf2 modulates the stress response and phenotype of malignant as well as premalignant pancreatic ductal epithelial cells by inducing expression of the ATF3 splicing variant ΔZip2. Oncogene 38, 1461–1476 (2019). https://doi.org/10.1038/s41388-018-0518-3

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