Protein kinase C activation by PMA rapidly induces apoptosis through caspase-3/CPP32 and serine protease(s) in a gastric cancer cell line.
Phorbol 12-myristate 13-acetate (PMA) rapidly induced cell death in SNU-16 gastric adenocarcinoma cells. DNA ladder formation and caspase-3/CPP32 activation were observed in PMA treated cells indicating that PMA induces apoptosis. z-DEVD-fmk, specific inhibitor of caspase-3/CPP32, inhibited the induction of apoptosis by PMA, demonstrating that caspase/CPP32 are critically involved in PMA-induced apoptosis. The serine protein inhibitor 4-(2-aminoethyl)benzenesulfonyl fluoride effectively blocked apoptosis, and also prevented caspase-3/CPP32 activation. Go6983, a specific inhibitor of PKC, almost completely suppressed apoptosis and caspase-3/CPP32 activation. Furthermore, 1,2-dihexanoyl-sn-glycerol, an endogenous activator of PKC, induced apoptosis detected by DNA fragmentation and Hoechst 33258 nuclear staining. From these results, we conclude that PMA is not only a tumor promoter, but can also induce apoptosis in gastric cancer cells. PMA-induced apoptosis appears to be mediated through activation of protein kinase C, and the activation of serine protease(s) and caspase-3/CPP32 may be the molecular mechanisms by which PMA induces apoptosis.
Park
I C
IC
Laboratory of Cell Biology, Korea Cancer Center Hospital, Seoul 139-240, Korea.
Park
M J
MJ
Rhee
C H
CH
Lee
J I
JI
Choe
T B
TB
Jang
J J
JJ
Lee
S H
SH
Hong
S I
SI
D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000096:biosynthesis*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D009363:Neoplasm Proteins / Q000187:drug effects* / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D013450:Sulfones / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D009363:Neoplasm Proteins; D015842:Serine Proteinase Inhibitors; D013450:Sulfones; C002010:4-(2-aminoethyl)benzenesulfonylfluoride; D017868:Cyclic AMP-Dependent Protein Kinases; D012697:Serine Endopeptidases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D013755:Tetradecanoylphorbol Acetate