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Arsenic Inhibits DNA Mismatch Repair by Promoting EGFR Expression and PCNA Phosphorylation

Dan Tong1, Janice Ortega2, Christine Kim2

  • 1From the College of Life Sciences, Wuhan University, Wuhan, China 430072, Department of Toxicology and Cancer Biology, Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky 40536, and Tsinghua University School of Medicine, Beijing, China 100084.

The Journal of Biological Chemistry
|April 25, 2015
PubMed

Insights

Arsenic exposure inhibits DNA mismatch repair (MMR) in human cells by affecting epidermal growth factor receptor (EGFR) and proliferating cell nuclear antigen (PCNA). This disruption may increase susceptibility to cancer from non-genotoxic carcinogens.

Area of Science:

  • Cellular biology
  • Toxicology
  • Carcinogenesis

Background:

  • Genotoxic and non-genotoxic chemicals can cause cancer, but the mechanisms of non-genotoxic carcinogens are not well understood.
  • Arsenic is a model non-genotoxic carcinogen whose cellular effects are under investigation.

Purpose of the Study:

  • To investigate the mechanism by which arsenic, a non-genotoxic carcinogen, contributes to cellular transformation.
  • To explore the role of DNA mismatch repair (MMR) in arsenic-induced carcinogenesis.

Main Methods:

  • Utilizing HeLa cells exposed to arsenic.
  • Measuring levels of epidermal growth factor receptor (EGFR) and tyrosine 211-phosphorylated proliferating cell nuclear antigen (PCNA).
  • Assessing DNA mismatch repair (MMR) activity in cell extracts and the effect of recombinant PCNA.

Main Results:

  • Arsenic exposure increased EGFR and phosphorylated PCNA levels in a dose- and time-dependent manner.
  • Cell extracts from arsenic-treated cells showed defective MMR activity.
  • Unphosphorylated PCNA restored normal MMR function, indicating PCNA phosphorylation inhibits MMR.

Conclusions:

  • Arsenic exposure stimulates EGFR, leading to PCNA phosphorylation and subsequent inhibition of MMR.
  • This mechanism suggests a novel pathway for non-genotoxic carcinogens like arsenic in promoting cancer.
  • Understanding this pathway could lead to new strategies for cancer prevention and treatment.
Keywords:
DNA mismatch repairDNA repairepidermal growth factor receptor (EGFR)nucleic acidproliferating cell nuclear antigen (PCNA)

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