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

Qiangsheng Hu1,2,3,4, Yi Qin1,2,3,4, Jinfeng Xiang1,2,3,4

  • 1Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.

Cell Proliferation
|April 28, 2018
PubMed
Abstract

Insights

Decreased deoxycytidine kinase (dCK) impacts pancreatic cancer by reducing NRF2 activity, leading to increased antioxidant gene expression and gemcitabine resistance. This creates a feedback loop that worsens treatment outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Deoxycytidine kinase (dCK) is crucial for gemcitabine metabolism and efficacy in pancreatic cancer.
  • Nuclear factor erythroid 2-related factor 2 (NRF2) regulates antioxidant genes and contributes to drug resistance.
  • The interplay between dCK and the NRF2 signaling pathway in pancreatic cancer remains underexplored.

Purpose of the Study:

  • To investigate the regulatory role of dCK in the NRF2 signaling axis.
  • To determine the impact of dCK on redox balance and reactive oxygen species (ROS) production.
  • To assess the correlation between dCK and NRF2 expression in pancreatic cancer and their effects on cell behavior.

Main Methods:

  • Overexpression of dCK in pancreatic cancer cell lines.
  • Assessment of NRF2 transcriptional activity and antioxidant gene expression.
  • Measurement of intracellular redox balance and ROS production.
  • Immunohistochemical analysis of patient tissues.
  • In vitro proliferation and metastasis assays.

Main Results:

  • dCK negatively regulates NRF2 transcriptional activity and expression of antioxidant genes.
  • dCK reduces intracellular redox balance and ROS production.
  • Inverse correlation observed between dCK and NRF2 levels in cell lines and patient samples.
  • dCK expression negatively impacts pancreatic cancer cell proliferation and metastasis.

Conclusions:

  • Reduced dCK expression enhances NRF2-driven antioxidant transcription.
  • This NRF2 activation contributes to gemcitabine treatment resistance in pancreatic cancer.
  • A feedback loop exists where decreased dCK promotes NRF2 activity, exacerbating drug resistance.
Keywords:
AREdCKNRF2ROSgemcitabinepancreatic cancer

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