An epidermal growth factor-ricin A chain (EGF-RTA)-resistant mutant and an epidermal growth factor-Pseudomonas endotoxin (EGF-PE)-resistant mutant have distinct phenotypes.
H2Oe12 is a mutant HeLa cell line selected for resistance to the toxicity of a chimeric protein conjugate composed of epidermal growth factor (EGF) and the toxic A chain of ricin (RTA). ET-28 is a mutant KB cell line selected for resistance to the toxicity of a chimeric protein conjugate composed of EGF and Pseudomonas exotoxin (PE). In this report we describe the presence or absence, in these mutants, of cross-resistance to the two toxic conjugates and the effects of ammonium chloride, leupeptin, and adenovirus cotreatments on toxin efficacies. ET-28 cells, the EGF-PE-resistant cells, are resistant to both EGF-PE and EGF-RTA. In contrast, H2Oe12 cells, the EGF-RTA-resistant cells, are as sensitive to EGF-PE toxicity as are their parent HeLa cells. Ammonium chloride cotreatment substantially reduces the resistance of H2Oe12 cells to EGF-RTA but has little or no effect on the resistance of ET-28 cells to either EGF-RTA or EGF-PE. Leupeptin has no effect on the toxicity of either chimeric conjugate on any of the four cell lines, effect on the toxicity of either chimeric conjugate on any of the four cell lines, despite its demonstrated ability to inhibit cellular degradation of EGF. In contrast, adenovirus cotreatment enhances the toxicity of EGF-RTA and EGF-PE on all cells tested, and completely nullifies the relative resistance of H2Oe12 and ET-28 cells to these toxic conjugates. H2Oe12 and ET-28 cells appear to be altered in distinct, possibly endosomal, functions.
Banker
D E
DE
Department of Biological Chemistry, UCLA School of Medicine 90024.
Pastan
I
I
Gottesman
M M
MM
Herschman
H R
HR
D036002:ADP Ribose Transferases; D000256:Adenoviridae / Q000502:physiology; D000643:Ammonium Chloride / Q000494:pharmacology; D001427:Bacterial Toxins; D004351:Drug Resistance; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005098:Exotoxins / Q000494:pharmacology*; D006367:HeLa Cells / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology*; D007976:Leupeptins / Q000494:pharmacology; D009154:Mutation; D010641:Phenotype; D011550:Pseudomonas aeruginosa; D012276:Ricin / Q000494:pharmacology*; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000643:Ammonium Chloride; D001427:Bacterial Toxins; D004815:Epidermal Growth Factor; D005098:Exotoxins; D000922:Immunotoxins; D007976:Leupeptins; D012276:Ricin; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C032854:leupeptin