Role of caspase 3-dependent Bcl-2 cleavage in potentiation of apoptosis by Bcl-2

• Published in: Molecular pharmacology Vol. 61; no. 1; p. 142
• Main Authors: Liang, Ye, Nylander, Karen D, Yan, Chaohua, Schor, Nina Felice
• Format: Journal Article
• Language: English
• Published: United States 01-01-2002
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis - physiology; Caspase 3; Caspase Inhibitors; Caspases - metabolism; Cisplatin - pharmacology; Cysteine Proteinase Inhibitors - pharmacology; Disease Models, Animal; Drug Interactions; Drug Screening Assays, Antitumor; Humans; Mice; Mice, Nude; Oligopeptides - pharmacology; PC12 Cells; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Proto-Oncogene Proteins c-bcl-2 - physiology; Rats; Transfection; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; Zinostatin - pharmacology
• ISSN: 0026-895X
• DOI: 10.1124/mol.61.1.142

Previous studies from our laboratory have demonstrated that Bcl-2 has a proapoptotic effect on neocarzinostatin (NCS)-treated PC12 pheochromocytoma cells. In the present study, we examine the mechanisms of this effect and demonstrate its relevance for the in vivo situation. Four hours after NCS treatment, a 23-kDa cleavage product of Bcl-2 was detected in whole cell lysates of bcl-2-transfected PC12 cells. In contrast, bcl-2 transfection protected PC12 cells from cisplatin-induced apoptosis, and cisplatin treatment did not result in Bcl-2 cleavage. Similarly, Bcl-2 cleavage did not occur and Bcl-2-mediated protection from, rather than potentiation of apoptosis was observed after NCS treatment of MCF-7 breast cancer cells. The caspase 3-specific inhibitor Ac-DEVD-CHO prevented Bcl-2 cleavage and attenuated NCS-induced apoptosis in bcl-2-transfected PC12 cells, whereas it had no effect on NCS-induced apoptosis in mock-transfected PC12 cells. Furthermore, MCF-7 cells do not express caspase 3, a finding in concert with the lack of Bcl-2 cleavage in this line. In in vivo experiments, xenografts of bcl-2-transfected PC12 cells were more susceptible to NCS toxicity than were xenografts of mock-transfected PC12 cells. Caspase 3-mediated Bcl-2 cleavage therefore plays an important role in the potentiation by Bcl-2 of NCS-induced apoptosis.