Activation of protein kinase C prevents induction of apoptosis by geranylgeraniol in human leukemia HL60 cells.
In a previous study, we showed that geranylgeraniol (GGO) is a potent inducer of apoptosis in human leukemia cells, including HL60 promyelocytic leukemia cells. The present study describes the effects of activators of protein kinase C (PKC) on GGO-induced apoptosis in various lines of leukemia cells. Both 12-O-tetradecanoylphorbol-13-acetate (TPA) and diacylglycerol (DG) inhibited the GGO-induced morphological changes that are characteristic of apoptosis and the DNA fragmentation. Similar effects were observed with other lines of human and murine leukemia cells such as ML1, U937, M1 and P388. Flow cytometric analysis also revealed that both TPA and DG prevented GGO-induced DNA degradation in a dose-dependent manner. These inhibitory effects of TPA and DG were antagonized by inhibitors of PKC such as H-7 and staurosporin, and by amiloride, an inhibitor of Na+/H+ antiporter. In contrast to the inhibitory effects of TPA and DG on GGO-induced apoptosis, 4alpha-TPA, which is unable to activate PKC, failed to prevent GGO-induced DNA fragmentation. However, the selective activator of PKC-beta, 12-deoxyphorbol 13-phenylacetate 20-acetate, significantly inhibited GGO-induced DNA fragmentation. Our results suggest that PKC, and in particular the PKC-beta isoenzyme, might be involved in the process of GGO-induced apoptosis.
Masuda
Y
Y
School of Pharmaceutical Sciences, Showa University, Shinagawa-ku, Tokyo, Japan.
Yoda
M
M
Ohizumi
H
H
Aiuchi
T
T
Watabe
M
M
Nakajo
S
S
Nakaya
K
K
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004075:Diglycerides / Q000494:pharmacology; D004224:Diterpenes / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007938:Leukemia / Q000473:pathology; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D004075:Diglycerides; D004224:Diterpenes; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D010703:Phorbol Esters; C029705:12-deoxyphorbolphenylacetate-20-acetate; D000584:Amiloride; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C017338:geranylgeraniol; D011493:Protein Kinase C; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate