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Constitutive nuclear factor-kappa B mRNA, protein overexpression and enhanced DNA-binding activity in thymidylate

W Wang1, J Cassidy

  • 1Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, UK. w.wang@beatson.gla.ac.uk

British Journal of Cancer
|February 20, 2003
PubMed

Insights

High constitutive nuclear factor kappa B (NF-kappa B) activity, driven by gene overexpression, is a key characteristic of thymidylate synthase (TS) inhibitor-resistant cancer cells, contributing to chemoresistance.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Pharmacology

Background:

  • Thymidylate synthase (TS) inhibitors are crucial in cancer therapy.
  • Acquired chemoresistance limits the efficacy of TS inhibitors.
  • The role of nuclear factor kappa B (NF-kappa B) in TS inhibitor resistance is not fully understood.

Purpose of the Study:

  • To investigate the role of nuclear factor kappa B (NF-kappa B) in thymidylate synthase (TS) inhibitor-resistant cancer cells.
  • To compare NF-kappa B gene copy number, mRNA, protein expression, and DNA-binding activity in resistant and wild-type cancer cell lines.

Main Methods:

  • Comparative analysis of gene copy number, mRNA, and protein expression of NF-kappa B subunits (p50 and p65).
  • Assessment of nuclear NF-kappa B DNA-binding activity using electrophoretic mobility shift assays.
  • Evaluation of NF-kappa B response to 5-fluorouracil (5-FU) in wild-type cells.

Main Results:

  • All tested TS inhibitor-resistant cell lines exhibited high constitutive NF-kappa B DNA-binding activity.
  • NF-kappa B overexpression (mRNA and protein) was observed in four out of five resistant cell lines.
  • Transient 5-FU exposure induced NF-kappa B DNA-binding activity in wild-type cells without altering protein levels.

Conclusions:

  • High constitutive NF-kappa B activity, often due to gene overexpression, is an intrinsic feature of TS inhibitor-resistant cancer cells.
  • NF-kappa B activation may antagonize chemotherapy-induced apoptosis, contributing to chemoresistance.
  • Elevated NF-kappa B expression and nuclear activity are implicated in the development of TS inhibitor resistance in cancer.

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