Phorbol esters inhibit low density lipoprotein processing by cultured human fibroblasts.
A 24 h pretreatment of MRC5 fibroblasts with the protein kinase C activator 12-O-tetradecanoylphorbol 13-acetate (TPA) induced a marked decrease in low density lipoprotein (LDL) internalization and degradation; the maximal effect (about 55% decrease) was observed for 10(-7) M TPA. LDL binding was reduced about 35-40%. A significant decrease (about 25%) in LDL internalization was observed after a 2 h incubation of cells with the drug, but longer incubation times (4-6 h) led to a greater effect. Another tumor promoter, phorbol 12,13-dibutyrate decreased LDL internalization by about 35%, whereas the non-tumor promoting 4 alpha-phorbol 12,13-didecanoate had no effect. The protein kinase C inhibitor alpha-cobrotoxin partially antagonized the inhibitory effect of TPA on LDL internalization. The non-phorbol tumor promoter mezerein, another protein kinase C activator, decreased LDL uptake by about 50%. Finally, it was found that TPA had no significant effect on the affinity of the receptor for the LDL. These results suggest a role for protein kinase C in the LDL pathway in cultured human fibroblasts.
D002460:Cell Line; D003039:Cobra Neurotoxin Proteins / Q000494:pharmacology; D004224:Diterpenes; D004705:Endocytosis / Q000187:drug effects; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D010703:Phorbol Esters / Q000494:pharmacology*; D011973:Receptors, LDL / Q000187:drug effects / Q000378:metabolism; D013729:Terpenes / Q000494:pharmacology
D003039:Cobra Neurotoxin Proteins; D004224:Diterpenes; D008077:Lipoproteins, LDL; D010703:Phorbol Esters; D011973:Receptors, LDL; D013729:Terpenes; C011309:mezerein