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Comparison of Caspase Activation and Subcellular Localization in HL-60 and K562 Cells Undergoing Etoposide-Induced Apoptosis
Luis M. Martins,
Peter W. Mesner,
Timothy J. Kottke,
Guriqbal S. Basi,
Sukanto Sinha,
Jay S. Tung,
Phyllis A. Svingen,
Benjamin J. Madden,
Atsushi Takahashi,
Daniel J. McCormick,
William C. Earnshaw, and
Scott H. Kaufmann
From the Institute of Cell & Molecular Biology, University of Edinburgh, Edinburgh, UK; the Division of Oncology Research and Protein Core Facility, Mayo Clinic, and the Department of Pharmacology, Mayo Medical School, Rochester, MN; and Athena Neurosciences, Inc, South San Francisco, CA.
Previous studies have shown that K562 chronic myelogenous leukemia cells are resistant to induction of apoptosis by a variety of agents, including the topoisomerase II (topo II) poison etoposide, when examined 4 to 24 hours after treatment with an initiating stimulus. In the present study, the responses of K562 cells and apoptosis-proficient HL-60 acute myelomonocytic leukemia cells to etoposide were compared, with particular emphasis on determining the long-term fate of the cells. When cells were treated with varying concentrations of etoposide for 1 hour and subsequently plated in soft agar, the two cell lines displayed similar sensitivities, with a 90% reduction in colony formation at 5 to 10 µmol/L etoposide. After treatment with 17 µmol/L etoposide for 1 hour, cleavage of the caspase substrate poly(ADP-ribose) polymerase (PARP), DNA fragmentation, and apoptotic morphological changes were evident in HL-60 cells in less than 6 hours. After the same treatment, K562 cells arrested in G2 phase of the cell cycle but otherwise appeared normal for 3 to 4 days before developing similar apoptotic changes. When the etoposide dose was increased to 68 µmol/L, apoptotic changes were evident in HL-60 cells after 2 to 3 hours, whereas the same changes were observed in K562 cells after 24 to 48 hours. This delay in the development of apoptotic changes in K562 cells was accompanied by delayed release of cytochrome c to the cytosol and delayed appearance of peptidase activity that cleaved the fluorogenic substrates Asp-Glu-Val-Asp-aminotrifluoromethylcoumarin (DEVD-AFC) and Val-Glu-Ile-Asp-aminomethylcoumarin (VEID-AMC) as well as an altered spectrum of active caspases that were affinity labeled with N-(N -benzyloxycarbonylglutamyl-N -biotinyllysyl) aspartic acid [(2,6-dimethylbenzoyl)oxy]methyl ketone [z-EK(bio)D-aomk]. On the other hand, the activation of caspase-3 under cell-free conditions occurred with indistinguishable kinetics in cytosol prepared from the two cell lines. Collectively, these results suggest that a delay in the signaling cascade upstream of cytochrome c release and caspase activation leads to a long latent period before the active phase of apoptosis is initiated in etoposide-treated K562 cells. Once the active phase of apoptosis is initiated, the spectrum and subcellular distribution of active caspase species differ between HL-60 and K562 cells, but a similar proportion of cells are ultimately killed in both cell lines.
Blood, Vol. 90 No. 11 (December 1), 1997:
pp. 4283-4296
© 1997 by The American Society of Hematology.
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