Mechanism of resistance to chemoradiation in p53 mutant human colon cancer.
To understand one of the mechanisms of resistance to chemoradiation in colon cancer cells, we investigated whether 5-fluorouracil (5-FU) mediated the expression of epidermal growth factor receptor (EGFR) and modified repair of radiation-induced DNA damage, especially in a p53 independent pathway. Cytotoxicity was determined for 5-FU combined with radiation for three colon cancer cell lines that contain mutant p53 (SW480, HT29 and WiDr), using the WST-8 colorimetric assay. EGFR and the excision repair cross complementation group 1 (ERCC1) proteins during chemoradiation were measured by Western blot analysis. SW480 cells were significantly resistant to chemoradiation compared to the other mutant p53 cell lines. The alteration of EGFR and ERCC1 proteins during chemoradiation in SW480 was apparently inversely related to that of the other radiosensitive cell lines. 5-FU-induced activation of EGFR followed by radiation in SW480 cells resulted in up-regulation of ERCC1. In contrast, 5-FU-induced degradation of EGFR followed by radiation in the other radiosensitive cell lines resulted in down-regulation of ERCC1. This suggested a complementary interaction between EGFR and ERCC1, and that 5-FU-induced EGFR activation conferred protection against radiation, through activation of DNA repair. Interaction of EGFR and ERCC1 might correlate with radiation-induced DNA damage when p53 mutant colon cancer cell lines are exposed to 5-FU followed by radiation.
Hiro
Junichiro
J
Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
Inoue
Yasuhiro
Y
Toiyama
Yuji
Y
Miki
Chikao
C
Kusunoki
Masato
M
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D015153:Blotting, Western; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000532:radiotherapy; D003131:Combined Modality Therapy; D004249:DNA Damage / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair / Q000187:drug effects / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004720:Endonucleases / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D011836:Radiation Tolerance; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
D000964:Antimetabolites, Antineoplastic; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D066246:ErbB Receptors; C071447:ERCC1 protein, human; D004720:Endonucleases; D005472:Fluorouracil