Role of Bcl-2 family proteins and caspase-3 in sanguinarine-induced bimodal cell death.
Sanguinarine, a benzophenanthridine alkaloid, has anticancer potential through induction of cell death. We previously demonstrated that sanguinarine treatment at a low level induced apoptosis or programmed cell death (PCD) in the Bcl-2 low-expressing K562 human erythroleukemia cells, and that a high level induced blister cell death (BCD); whereas Bcl-2 overexpressing, sanguinarine-treated JM1 pre-B lymphoblastic cells displayed neither apoptosis nor BCD morphologies. Here, we report that sanguinarine-treated K562 cells, when analyzed by western blot, showed significant increase in expression of the pro-apoptotic Bax protein in apoptosis, but not in BCD. cDNA expression array of PCD in K562 cells failed to reveal the presence of Bax at the gene transcript level, which suggests that this cell death process does not require de novo protein synthesis. Treated JM1 cells, on the other hand, showed an increase in the expression of Bcl-2 protein in both forms of cell death, but failed to show Bax expression. The role of other members of the Bcl-2 family remained negligible. Caspase-3 activation was observed in apoptosis of K562 cells but not in BCD or in sanguinarine-treated JM1 cells. These results suggest that sanguinarine in K562 cells induces apoptosis through increasing Bax and activating caspase-3, whereas sanguinarine-induced BCD involves neither. These results also suggest that in JM1 cells, Bcl-2 may play a role in susceptibility of cells to induction of apoptosis and BCD.
Weerasinghe
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Faculty of Medicine, Memorial University of Newfoundland, Canada. priyaw@mit.edu
Hallock
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Tang
S C
SC
Liepins
A
A
D000470:Alkaloids / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053119:Benzophenanthridines; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D006801:Humans; D007546:Isoquinolines; D020014:K562 Cells; D010617:Phenanthridines / Q000494:pharmacology; D011289:Preleukemia / Q000648:ultrastructure; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
D000470:Alkaloids; C494826:BAX protein, human; D053119:Benzophenanthridines; D007546:Isoquinolines; D010617:Phenanthridines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C005705:sanguinarine; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases