Nrf2 is overexpressed in pancreatic cancer: implications for cell proliferation and therapy

Molecular Cancer

Research

Bryony Lloyd¹  Ian M Copple²  Samantha Williams²  Neil R Kitteringham²  B Kevin Park²  Adam Lister²  Chris E Goldring²  Andrew Owen²  Fiona Campbell³  Taoufik Nedjadi⁴  Eithne Costello⁴  John P Neoptolemos⁴ 

[1] Applied Cancer Biology Group, Liverpool CR-UK Centre and Division of Surgery and Oncology, University of Liverpool, UK;MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, UK;The Liverpool CR-UK Centre, Division of Pathology, University of Liverpool, UK;The Liverpool NIHR Pancreas Biomedical Research Unit. The Liverpool Experimental Cancer Medicine Centre, Liverpool CR-UK Centre and Division of Surgery and Oncology, University of Liverpool, UK;

关键词: Pancreatic Cancer;    Gemcitabine;    Pancreatic Cancer Cell;    Pancreatic Ductal Adenocarcinoma;    Pancreatic Cancer Cell Line;   

DOI  :  10.1186/1476-4598-10-37

 received in 2010-06-15, accepted in 2011-04-13,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundNrf2 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.ResultsKeap1, 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).ConclusionsExpression 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.

【 授权许可】

Unknown   
© Lister et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.