Keap1–Nrf2 signalling in pancreatic cancer

Hayes, Alastair; Skouras, Christos; Haugk, Beate; Charnley, Richard

doi:10.1016/j.biocel.2015.06.017

Cited by 48 publications

(40 citation statements)

References 131 publications

(211 reference statements)

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“…Thus, a dCK-NRF2/ARE feedback loop exists, which collectively renders pancreatic cancer cells gemcitabine resistant we deduced that in addition to the role of dCK in gemcitabine metabolism, this kinase may also contribute to drug resistance by regulating ROS production and the NRF2/ARE axis, which synergistically regulate intrinsic and acquired gemcitabine resistance in pancreatic cancer cells. Previous studies have demonstrated that NRF2 activation is the net result of oncogenic Kras mutation and MAPK pathway activation 29. Consistent with this finding, we also observed a decrease in ERK1/2 activation in dCK-overexpressing PANC-1 and MIA PaCa-2 cells.…”

supporting

confidence: 92%

dCK negatively regulates the NRF2/ARE axis and ROS production in pancreatic cancer

Qin

Xiang

et al. 2018

Cell Proliferation

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Objectives: Decreased deoxycytidine kinase (dCK) expression is a reported indicator of gemcitabine efficacy in pancreatic cancer, due to the impact of this kinase on gemcitabine metabolism. The transcription factor NF-E2 p45-related factor 2 (NRF2, also called Nfe2l2), a master regulator of redox homoeostasis, has been reported to tightly control the expression of numerous ROS-detoxification genes and participates in drug resistance. However, the contribution of dCK to the NRF2 signalling axis has seldom been discussed and needs investigation. Materials and methods:By overexpressing dCK in pancreatic cancer cells, we assessed the impact of dCK on NRF2 transcriptional activity. Furthermore, we measured the impact of dCK expression on the intracellular redox balance and reactive oxygen species (ROS) production. By utilizing immunohistochemical staining and tissues from pancreatic cancer patients, we assessed the correlation between dCK and NRF2 expression. Through proliferation and metastasis assays, we examined the impact of dCK expression on cell proliferation and metastasis.Results: dCK negatively regulates NRF2 transcriptional activity, leading to the decreased expression of ARE-driven antioxidant genes. In addition, dCK negatively regulates intracellular redox homoeostasis and ROS production. Negative correlations between dCK and NRF2 levels in pancreatic cancer cell lines and patient samples were observed. In vitro cell line studies suggested that dCK negatively regulated proliferation and metastasis. Conclusion:Decreased dCK expression promotes NRF2-driven antioxidant transcription, which further enhances gemcitabine treatment resistance, forming a feedback loop.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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supporting

confidence: 92%

dCK negatively regulates the NRF2/ARE axis and ROS production in pancreatic cancer

Qin

Xiang

et al. 2018

Cell Proliferation

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“…NRF2 and the ARE-driven genes it controls are frequently upregulated in PDAC and correlate with poor survival. Upregulation of NRF2 is, at least in part, Kras-driven and contributes to proliferation and chemoresistance in PDAC (21,22).…”

Section: Introductionmentioning

confidence: 99%

PIN1 Maintains Redox Balance via the c-Myc/NRF2 Axis to Counteract Kras-Induced Mitochondrial Respiratory Injury in Pancreatic Cancer Cells

Liang

Shi

et al. 2019

Cancer Research

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Kras is a decisive oncogene in pancreatic ductal adenocarcinoma (PDAC). PIN1 is a key effector involved in the Kras/ERK axis, synergistically mediating various cellular events. However, the underlying mechanism by which PIN1 promotes the development of PDAC remains unclear. Here we sought to elucidate the effect of PIN1 on redox homeostasis in Kras-driven PDAC. PIN1 was prevalently upregulated in PDAC and predicted the prognosis of the disease, especially Kras-mutant PDAC. Downregulation of PIN1 inhibited PDAC cell growth and promoted apoptosis, partially due to mitochondrial dysfunction. Silencing of PIN1 damaged basal mitochondrial function by significantly increasing intracellular ROS. Furthermore, PIN1 maintained redox balance via synergistic activation of c-Myc and NRF2 to upregulate expression of antioxidant response element driven genes in PDAC cells. This study elucidates a new mechanism by which Kras/ERK/NRF2 promotes tumor growth and identifies PIN1 as a decisive target in therapeutic strategies aimed at disturbing the redox balance in pancreatic cancer.Significance: This study suggests that antioxidation protects Kras-mutant pancreatic cancer cells from oxidative injury, which may contribute to development of a targeted therapeutic strategy for Kras-driven PDAC by impairing redox homeostasis.

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“…Temporary activation of NRF2 could protect normal cells from toxins or carcinogens, however, sustained activation of NRF2 will upregulate the expression of downstream genes, thus providing a conducive environment for malignant cells and facilitating cancer progression . Previous research has demonstrated that abnormal activation of NRF2 is associated with lung, breast, bladder, ovarian, pancreatic, and endometrial cancers and liver cancer metastasis . Contrarily, silencing of NRF2 in tumor cells would lead to decreased cell migration and metastasis potential.…”

Section: Discussionmentioning

confidence: 99%

“…9,10 Previous research has demonstrated that abnormal activation of NRF2 is associated with lung, breast, bladder, ovarian, pancreatic, and endometrial cancers and liver cancer metastasis. [24][25][26][27][28][29] Contrarily, silencing of NRF2 in tumor cells would lead to decreased cell migration and metastasis potential.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of NRF2 is correlated with prognoses of patients with malignancies: A meta‐analysis

Guo

Shen

2017

Thoracic Cancer

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BackgroundPrevious published research has demonstrated that NRF2 expression is a poor prognostic factor for many malignancies. However, because of the small sample enrolled in a single study, it is difficult to draw valuable conclusions. Therefore, we hypothesized that NRF2 overexpression in cancer tissues may be associated with the prognoses of patients with solid malignancies, and conducted a systemic review and meta‐analysis.MethodsA comprehensive search of PubMed, Web of Science, Science Direct, Embase, and Ovid databases for relevant studies regarding the role of NRF2 expression in solid malignancies was conducted. Hazard ratios (HR) and 95% confidence intervals (CIs) were extracted from these studies to provide pooled estimates of the effect of NRF2 expression on patients’ overall and disease‐free survival.ResultsNine studies met the criteria for analysis. Statistical analysis demonstrated that compared to patients with low NRF2 expression, patients with overexpression of NRF2 had poorer overall survival (HR 2.01, 95% CI 1.57–2.56; P < 0.001) and disease‐free survival (HR 3.25, 95% CI 1.29–8.15; P = 0.025).ConclusionPublished evidence of the role of NRF2 expression in survival of cancer patients is limited. This analysis supports the view that NRF2 overexpression is a poor prognostic factor for solid malignancies, thus optimizing treatment for patients with NRF2 overexpression may improve their overall survival.

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Keap1–Nrf2 signalling in pancreatic cancer

Cited by 48 publications

References 131 publications

dCK negatively regulates the NRF2/ARE axis and ROS production in pancreatic cancer

dCK negatively regulates the NRF2/ARE axis and ROS production in pancreatic cancer

PIN1 Maintains Redox Balance via the c-Myc/NRF2 Axis to Counteract Kras-Induced Mitochondrial Respiratory Injury in Pancreatic Cancer Cells

Overexpression of NRF2 is correlated with prognoses of patients with malignancies: A meta‐analysis

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