Failure to activate caspase 3 in phorbol ester-resistant leukemia cells is associated with resistance to apoptotic cell death.
The protein kinase C (PKC)-specific inhibitor, Ro-31-8220, has been shown to induce anti-proliferation and apoptosis of human cancer cell lines. In the present study, we determined the molecular pathways that lead to apoptosis after treatment of cells with the PKC-specific inhibitor RO-31-8220. For this, we used the U937 human leukemia cell line and a phorbolmyristate acetate (PMA)-resistant derivative cell line, R-U937. Ro-31-8220 treatment of U937 cells leads to apoptosis, which is accompanied by activation of caspase 3 (as measured by decreased levels of the 32kDa inactive form and increased proteolytic cleavage of phospholipase C (PLC)-gamma1). The broad-range caspase inhibitor z-VAD-fmk inhibits this induction of apoptosis, supporting a direct link between caspase activation and Ro-31-8220 induction of apoptosis. This activation of apoptosis is also accompanied by release of cytochrome c, but not by altered expression of Bcl-2 family protein or IAP family proteins. In R-U937 cells, Ro-31-8220 fails to cause release of cytochrome c, activation of caspase 3, or apoptosis. Activation of Akt occurs to a greater extent in the R-U937 cells than the U937 cells and thus might be related to protection from Ro-31-8220-induced apoptosis.
Choi
Yun-Jung
YJ
Department of Immunology, School of Medicine, Keimyung University, 194 DongSan-Dong Jung-Gu, 700-712, Taegu, South Korea.
Park
Jong-Wook
JW
Woo
Ju-Hyung
JH
Kim
Young-Ho
YH
Lee
Sang-Han
SH
Lee
Jin-Man
JM
Kwon
Taeg Kyu
TK
D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002467:Cell Nucleus / Q000187:drug effects / Q000473:pathology; D004351:Drug Resistance; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity*; D020298:U937 Cells
D004791:Enzyme Inhibitors; D007211:Indoles; D011493:Protein Kinase C; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D013755:Tetradecanoylphorbol Acetate; C064758:Ro 31-8220