Failure to activate caspase 3 in phorbol ester-resistant leukemia cells is associated with resistance to apoptotic cell death

• Published in: Cancer letters Vol. 182; no. 2; pp. 183 - 191
• Main Authors: Choi, Yun-Jung, Park, Jong-Wook, Woo, Ju-Hyung, Kim, Young-Ho, Lee, Sang-Han, Lee, Jin-Man, Kwon, Taeg Kyu
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 28.08.2002; Elsevier; Elsevier Limited
• Subjects: Akt; Antineoplastic agents; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Caspase 3; Caspases - metabolism; Cell cycle; Cell Nucleus - drug effects; Cell Nucleus - pathology; Chemotherapy; Cloning; Deoxyribonucleic acid; Disease; DNA; Drug Resistance; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Humans; Indoles - pharmacology; Kinases; Medical sciences; Membranes; Mitochondria; Pharmacology. Drug treatments; Protein Kinase C - antagonists & inhibitors; Protein kinase C inhibitor; Proteins; Tetradecanoylphorbol Acetate - toxicity; U937 Cells; Protein kinase C inhibitor; Caspase 3; Akt; Cell cycle; Apoptosis; Antineoplastic agent; Human; Cell proliferation; Protein kinase C; Enzyme; Transferases; Leukemia; Caspase; Enzyme inhibitor; Malignant hemopathy; In vitro; Biological activity; Resistance; Peptidases; Signal transduction; Specificity; Sensitivity resistance; Cell death; Established cell line; Hydrolases; Mechanism of action; Tumor cell
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/S0304-3835(02)00082-4

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 32 kDa inactive form and increased proteolytic cleavage of phospholipase C (PLC)-γ1). 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.