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

• Published in: Radiation research Vol. 159; no. 4; p. 439
• Main Authors: Yacoub, Adly, McKinstry, Robert, Hinman, Darin, Chung, Theodore, Dent, Paul, Hagan, Michael P
• Format: Journal Article
• Language: English
• Published: United States 01.04.2003
• Subjects: 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; Flavonoids - pharmacology; Gamma Rays; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - radiation effects; Humans; Male; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; MAP Kinase Signaling System - radiation effects; 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; Receptor, Epidermal Growth Factor - drug effects; Receptor, Epidermal Growth Factor - physiology; Tumor Cells, Cultured - drug effects; Tumor Cells, Cultured - metabolism; Tumor Cells, Cultured - radiation effects; Tyrphostins - pharmacology; X-ray Repair Cross Complementing Protein 1
• ISSN: 0033-7587
• DOI: 10.1667/0033-7587(2003)159[0439:EGFAIR]2.0.CO;2

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.