Abstract
Sensitivity of tumor cells to anticancer therapy depends on the ability of the drug to induce apoptosis. However, multiple signaling pathways control this induction and thus determine this sensitivity. We report here that staurosporine, a well known inducer of apoptosis in a wide range of cell lines, displays distinct ability to trigger apoptosis in two different L1210 sublines (termed L1210/S and L1210/0). Staurosporine treatment resulted in an early cell death (within 3 h) in L1210/S cells, while in L1210/0 cells, death occurred only after 12 h. In both instances, death occurred by apoptosis. A broad spectrum caspase inhibitor, Z-VAD-fmk, blocked early apoptosis in L1210/S cells but did not confer any protection on late apoptosis in L1210/0 cells. Protection by Z-VAD-fmk observed in L1210/S cells was not lasting and unmasked a secondary process of cell death that also exhibited characteristics of apoptosis. Thus, staurosporine induces apoptotic cell death through at least two redundant parallel pathways. These two pathways normally coexist in L1210/S cells. However, the early cell death mechanism depending on caspase activation disguises the late caspase-independent apoptotic process. Staurosporine-induced apoptosis in L1210/0 cells develops only by the caspase-independent mechanism due to a general defect in caspase activation.
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Acknowledgements
We thank Dr A Eastman (Dartmouth, USA) and Dr S Cros (Toulouse, France) for generously providing the L1210/0 and L1210/S cell lines. We wish to aknowledge the assistance of Dr Macarena Robledo (INSERM EMI 003) who performed the flow cytometry analysis. Special acknowledgment is given to Dr M Lanotte (INSERM U496) for many helpful discussions and comments on this manuscript. This work was supported in part by grants from the Association pour la Recherche contre le Cancer (Villejuif, France) and from the Ligue Nationale contre le Cancer (Paris, France). CA Belmokhtar is supported by a Ligue Nationale contre le Cancer fellowship.
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Belmokhtar, C., Hillion, J. & Ségal-Bendirdjian, E. Staurosporine induces apoptosis through both caspase-dependent and caspase-independent mechanisms. Oncogene 20, 3354–3362 (2001). https://doi.org/10.1038/sj.onc.1204436
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DOI: https://doi.org/10.1038/sj.onc.1204436
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