Differential mechanism for the inhibition of epidermal growth factor binding to its receptor on mouse keratinocytes by anthrones and phorbol esters.
1,8-Dihydroxy-3-methyl-9-anthrone (chrysarobin), a potent anthrone tumor promoter, reduced [125I] epidermal growth factor (EGF) binding to its receptor in primary epidermal cells from SENCAR mice maintained in low Ca2+ containing medium. The time course for this effect with chrysarobin was different from that of 12-O-tetradecanoylphorbol-13-acetate (TPA). Maximum inhibition of [125I]EGF binding was observed at 18 h versus 1 h respectively. Scatchard analyses revealed that the inhibition by chrysarobin was due to a decrease in the number of both high- and low-affinity classes of EGF receptors. In contrast, TPA caused a rapid inhibition of EGF binding, primarily due to a loss of high-affinity receptors. The mechanism by which chrysarobin inhibited the binding of EGF to its receptor involved neither direct activation nor membrane translocation of epidermal protein kinase C, whereas the rapid decrease in EGF binding induced by TPA was consistent with its ability to activate protein kinase C. Structure-activity relationships for EGF binding inhibition by anthrones revealed that inhibition was inversely proportional to chain length at the C10-position, which correlated closely with oxidation rate and skin tumor-promoting activity. alpha-Tocopherol was able to block partially the effect of chrysarobin but not TPA on EGF binding. These results suggest that oxidation at position C10 is at least partially responsible for the inhibition of EGF binding induced by chrysarobin. Furthermore, these studies support the hypothesis that changes in EGF receptor binding and/or function may play a role in skin tumor promotion by diverse classes of promoting agents.
University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville 78957.
A
A
Imamoto
L M
LM
Beltrán
J
J
DiGiovanni
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology*; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000378:metabolism*; D066246:ErbB Receptors / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D015603:Keratinocytes / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D008815:Mice, Inbred Strains; D011493:Protein Kinase C / Q000378:metabolism; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014810:Vitamin E / Q000494:pharmacology
D000873:Anthracenes; D002273:Carcinogens; D014810:Vitamin E; D004815:Epidermal Growth Factor; C013883:chrysarobin; D066246:ErbB Receptors; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate