Role of caspase 3-dependent Bcl-2 cleavage in potentiation of apoptosis by Bcl-2.
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
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.
Date: Jan. 01, 2002
PubMed ID: 11752215
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