Inhibition of 12-O-tetradecanoylphorbol-13-acetate-stimulated 32Pi incorporation into phospholipids and protein phosphorylation by 2,7,11-cembratriene-4,6-diol, an antitumor-promoting agent.
A possible mechanism of antitumor-promoting activity of alpha-2,7,11-cembratriene-4,6-diol (alpha-CBT) was studied. alpha-CBT inhibited the 32Pi incorporation into phospholipids of HeLa cells stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA). In contrast to the property to interact with calmodulin of many other antitumor-promoting agents, which were proved to inhibit TPA-stimulated 32Pi incorporation into phospholipids, alpha-CBT did not show any interaction with calmodulin; i.e., the fluorescence of N-phenyl-1-naphthylamine enhanced by binding with Ca2+-calmodulin was not influenced by treatment with alpha-CBT. TPA-stimulated phosphorylation of 47-kilodalton protein, which is phosphorylated by protein kinase C in human platelets, was found to be inhibited by alpha-CBT. However, the specific binding of 3H-TPA to mouse epidermal particulate fraction was not inhibited by treatment with alpha-CBT. These results suggest that alpha-CBT inhibits the activity of protein kinase C by another mode of action rather than the effect on its receptor site, and that this action and calmodulin-independent inhibitory effect on phospholipid metabolism of alpha-CBT may play a certain role in its antitumor-promoting activity in vivo.
Saito
Y
Y
Central Research Institute, Japan Tobacco Inc., Yokohama.
Nishino
H
H
Yoshida
D
D
Mizusaki
S
S
Ohnishi
A
A
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002147:Calmodulin / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D005453:Fluorescence; D006367:HeLa Cells; D006801:Humans; D010710:Phosphates / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism*; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D000970:Antineoplastic Agents; D002147:Calmodulin; D004224:Diterpenes; D010710:Phosphates; D010743:Phospholipids; D011506:Proteins; C046139:2,7,11-cembratriene-4,6-diol; D013755:Tetradecanoylphorbol Acetate