Hypotheses on the molecular mechanism of action of tumor promoters.
This paper presents hypotheses concerning the molecular basis for tumor promotion. Phorbol and related ingenol esters fall into two groups - (a) those that are inflammatogens alone, and (b) those that are both inflammatogens and tumor promoters. Both of these are complementary to lipophilic groove A on the molecules of PLA2 and pro-PLA2. The difference between groups (a) and (b) lies significantly in the nature of the long hydrocarbon side chain. In compounds in group (a) these side chains are flexible or fixed curled over the body of the molecule; in compounds in group (b) they are inflexible (double-bonded). This suggests that an interaction with the lipid bilayer may be significant for State 1 promotion as a necessary, but not sufficient, factor for tumor promotion. Stage 2 promotion (also necessary, but not sufficient in itself) may involve activation of PLA2, possibly by activation or pronase. Possible receptor sites for TPA are reviewed to include a hypothetical external membrane receptor, PLA2, pro- PLA2, and PLC, as well as the possible nature of the endogenous ligand at the "TPA receptor" to include a phospholipid and a polypeptide.
D000818:Animals; D002273:Carcinogens; D006801:Humans; D007249:Inflammation; D008954:Models, Biological; D008968:Molecular Conformation; D010741:Phospholipases A; D054467:Phospholipases A2; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate
D002273:Carcinogens; D010741:Phospholipases A; D054467:Phospholipases A2; D013755:Tetradecanoylphorbol Acetate