title: Nrf2 is overexpressed in pancreatic cancer: implications for cell proliferation and therapy.
abstract: BACKGROUND
  Nrf2 is a key transcriptional regulator of a battery of genes that facilitate phase II/III drug metabolism and defence against oxidative stress. Nrf2 is largely regulated by Keap1, which directs Nrf2 for proteasomal degradation. The Nrf2/Keap1 system is dysregulated in lung, head and neck, and breast cancers and this affects cellular proliferation and response to therapy. Here, we have investigated the integrity of the Nrf2/Keap1 system in pancreatic cancer.
  
  
  RESULTS
  Keap1, Nrf2 and the Nrf2 target genes AKR1c1 and GCLC were detected in a panel of five pancreatic cancer cell lines. Mutation analysis of NRF2 exon 2 and KEAP1 exons 2-6 in these cell lines identified no mutations in NRF2 and only synonomous mutations in KEAP1. RNAi depletion of Nrf2 caused a decrease in the proliferation of Suit-2, MiaPaca-2 and FAMPAC cells and enhanced sensitivity to gemcitabine (Suit-2), 5-flurouracil (FAMPAC), cisplatin (Suit-2 and FAMPAC) and gamma radiation (Suit-2). The expression of Nrf2 and Keap1 was also analysed in pancreatic ductal adenocarcinomas (n = 66 and 57, respectively) and matching normal benign epithelium (n = 21 cases). Whilst no significant correlation was seen between the expression levels of Keap1 and Nrf2 in the tumors, interestingly, Nrf2 staining was significantly greater in the cytoplasm of tumors compared to benign ducts (P < 0.001).
  
  
  CONCLUSIONS
  Expression of Nrf2 is up-regulated in pancreatic cancer cell lines and ductal adenocarcinomas. This may reflect a greater intrinsic capacity of these cells to respond to stress signals and resist chemotherapeutic interventions. Nrf2 also appears to support proliferation in certain pancreatic adenocarinomas. Therefore, strategies to pharmacologically manipulate the levels and/or activity of Nrf2 may have the potential to reduce pancreatic tumor growth, and increase sensitivity to therapeutics.
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Lister
authors.forename: Taoufik
authors.initials: T
authors.lastname: Nedjadi
authors.forename: Neil R
authors.initials: NR
authors.lastname: Kitteringham
authors.forename: Fiona
authors.initials: F
authors.lastname: Campbell
authors.forename: Eithne
authors.initials: E
authors.lastname: Costello
authors.forename: Bryony
authors.initials: B
authors.lastname: Lloyd
authors.forename: Ian M
authors.initials: IM
authors.lastname: Copple
authors.forename: Samantha
authors.initials: S
authors.lastname: Williams
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
authors.forename: John P
authors.initials: JP
authors.lastname: Neoptolemos
authors.forename: Chris E
authors.initials: CE
authors.lastname: Goldring
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005091:Exons; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human