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Requirement for caspase activation in monocytic differentiation of myeloid leukemia cells

Oncogene volume 19, pages 3941–3947 (2000)Cite this article

Abstract

Human myeloid leukemia cells respond to 12-tetradecanoylphorbol-13-acetate (TPA) and other activators of protein kinase C (PKC) with the induction of terminal monocytic differentiation. The present studies demonstrate that TPA treatment of U-937 leukemia cells is associated with release of mitochondrial cytochrome c, activation of caspase-3 and induction of internucleosomal DNA fragmentation. By contrast, the TUR cell variant, which is deficient in PKCβ, failed to respond to TPA with release of cytochrome c and induction of the caspase-3 cascade. Moreover, stable overexpression of PKCβ in TUR cells reconstituted sensitivity to TPA-induced cytochrome c release and activation of caspase-3. The results also demonstrate that treatment of cells with the caspase inhibitor Z-VAD-fmk blocks both TPA-induced apoptosis and monocytic differentiation. Similar results were obtained in U-937 cells stably expressing the CrmA caspase inhibitor. These findings demonstrate that TPA induces cytochrome c release by a PKCβ-dependent mechanism and that activation of caspase-mediated signaling is required for induction of the differentiated monocytic phenotype.

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Abbreviations

PKC:

protein kinase C

TPA:

12-O-tetradecanoylphorbol-13-acetate

Bid:

Bcl-2 interacting protein

cyt c:

cytochrome c

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Acknowledgements

This investigation was supported by PHS grants CA42802 and CA29431 awarded by the National Cancer Institute, DHHS.

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Authors and Affiliations

  1. Dana-Farber Cancer Institute, Harvard Medical School, Boston, 02115, Massachusetts, MA, USA

    Pramod Pandey, Atsuko Nakazawa, Yasumasa Ito, Rakesh Datta, Surender Kharbanda & Donald Kufe

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  1. Pramod Pandey
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  2. Atsuko Nakazawa
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Pandey, P., Nakazawa, A., Ito, Y. et al. Requirement for caspase activation in monocytic differentiation of myeloid leukemia cells. Oncogene 19, 3941–3947 (2000). https://doi.org/10.1038/sj.onc.1203751

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