Epidermal growth factor and ionizing radiation up-regulate the DNA repair genes XRCC1 and ERCC1 in DU145 and LNCaP prostate carcinoma through MAPK signaling

Radiat Res. 2003 Apr;159(4):439-52. doi: 10.1667/0033-7587(2003)159[0439:egfair]2.0.co;2.

Abstract

This work examined the importance of radiation-induced and ligand-induced EGFR-ERK signaling for the regulation of DNA repair proteins XRCC1 and ERCC1 in prostate carcinoma cells, DU145 (TP53(mut)), displaying EGFR-TGFA-dependent autocrine growth and high MAPK (ERK1/2) activity, and LNCaP (TP53(wt)) cells expressing low constitutive levels of ERK1/2 activity. Using quantitative RT-PCR and Western analyses, we determined that ionizing radiation activated the DNA repair genes XRCC1 and ERCC1 in an ERK1/2-dependent fashion for each cell line. After irradiation, a rapid increase followed by a decrease in ERK1/2 activity preceded the increase in XRCC1/ERCC1 expression in DU145 cells, while only the rapid decrease in ERK1/2 preceded the increase in XRCC1/ERCC1 expression in LNCaP cells. Administration of EGF, however, markedly increased the up-regulation of phospho-ERK, ERCC1 and XRCC1 in both cell lines. Although the EGFR inhibitor tyrphostin (AG-1478) and the MEK inhibitor PD90859 both attenuated EGF-induced levels of the ERCC1 and XRCC1 protein, PD98059 blocked the induction of ERCC1 and XRCC1 by radiation more effectively in both cell lines. Inhibition of ERK at a level that reduced the up-regulation of DNA repair led to the persistence of apurinic/apyrimidinic (AP) sites of DNA damage and increased cell killing. Taken together, these data imply a complex control of DNA repair activation that may be more generally dependent on MAPK (ERK1/2) signaling than was previously noted. These data provide novel insights into the capacity of the EGFR-ERK signaling to modulate DNA repair in cancer cells and into the functional significance of this signaling.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenocarcinoma / pathology*
  • Autocrine Communication
  • Cobalt Radioisotopes
  • DNA Damage
  • DNA Repair / drug effects
  • DNA Repair / physiology*
  • DNA Repair / radiation effects
  • DNA-Binding Proteins / biosynthesis*
  • DNA-Binding Proteins / genetics
  • Endonucleases*
  • Enzyme Inhibitors / pharmacology
  • Epidermal Growth Factor / pharmacology*
  • ErbB Receptors / drug effects
  • ErbB Receptors / physiology*
  • Flavonoids / pharmacology
  • Gamma Rays*
  • Gene Expression Regulation, Neoplastic* / drug effects
  • Gene Expression Regulation, Neoplastic* / radiation effects
  • Humans
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology*
  • MAP Kinase Signaling System / radiation effects
  • Male
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / metabolism*
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / drug effects
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Prostatic Neoplasms / pathology*
  • Protein Biosynthesis*
  • Proteins / genetics
  • Quinazolines
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism
  • Tumor Cells, Cultured / radiation effects
  • Tyrphostins / pharmacology
  • X-ray Repair Cross Complementing Protein 1

Substances

  • Cobalt Radioisotopes
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Flavonoids
  • Neoplasm Proteins
  • Proteins
  • Quinazolines
  • Tyrphostins
  • X-ray Repair Cross Complementing Protein 1
  • XRCC1 protein, human
  • RTKI cpd
  • Epidermal Growth Factor
  • ErbB Receptors
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • ERCC1 protein, human
  • Endonucleases
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one