Epidermal growth factor induction of resistance to topoisomerase II toxins in human squamous carcinoma A431 cells.
Alteration of the epidermal growth factor (EGF) signaling pathway occurs frequently in human cancer cells and may subsequently affect the cell survival towards anti-cancer agents. To elucidate the effect of long-term EGF treatment on the chemo-sensitivity of human cancer cells, human squamous carcinoma A431 cells (AP) were incubated continuously with 50 ng/ml EGF for 30 weeks and these cells were designated as the AC cells. The long-term EGF treatment did not alter the EGFR level and the EGF-induced protein tyrosine phosphorylation pattern in the AC cells. By MTT assay, the AC cells were shown to be more resistant than the AP cells to doxorubicin, etoposide and amsacrine but not to cisplatin. Among the drug-resistant proteins, topoisomerase IIalpha (topoII) was downregulated in the AC cells while there was no apparent change in the levels of P-glycoprotein, MRP-1 or glutathione- S-transferase-pi as compared to the AP cells. Furthermore, knockdown of topoII by antisense topoII oligonucleotide transfection decreased the sensitivity to doxorubicin, etoposide and amsacrine in the A431 cells. Results from the present study support an idea that long-term treatment with EGF may induce drug resistance in cells through the downregulation of topoII.
Tsang
Wing-Pui
WP
Department of Biochemistry, The Chinese University of Hong Kong, Hong Kong SAR, P.R. China.
Kong
Siu-Kai
SK
Kwok
Tim-Tak
TT
D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D004815:Epidermal Growth Factor / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009841:Oligonucleotides / Q000737:chemistry; D010766:Phosphorylation; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014443:Tyrosine / Q000737:chemistry
D009841:Oligonucleotides; D013778:Tetrazolium Salts; D013844:Thiazoles; D014443:Tyrosine; D004815:Epidermal Growth Factor; D004250:DNA Topoisomerases, Type II; C022616:thiazolyl blue