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

The Pediatric Center for Neuroscience, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
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.
Mesh Terms:
Animals, Antineoplastic Agents, Apoptosis, Caspase 3, Caspases, Cisplatin, Cysteine Proteinase Inhibitors, Disease Models, Animal, Drug Interactions, Drug Screening Assays, Antitumor, Humans, Mice, Mice, Nude, Oligopeptides, PC12 Cells, Proto-Oncogene Proteins c-bcl-2, Rats, Transfection, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Zinostatin
Mol. Pharmacol. Jan. 01, 2002; 61(1);142-9 [PUBMED:11752215]
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