Enhancement of susceptibility to Fas-mediated apoptosis in HL-60 cells through down-regulation of cellular FLICE-inhibitory protein by phosphatidylinositol 3-kinase inhibitors

  • Authors:
    • Gen Kondo
    • Masayasu Iwase
    • Hitoshi Watanabe
    • Makiko Uchida
    • Sayaka Takaoka
    • Masaru Ohashi
    • Daisuke Ito
    • Masao Nagumo
  • View Affiliations

  • Published online on: November 1, 2005     https://doi.org/10.3892/or.14.5.1215
  • Pages: 1215-1222
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Abstract

Promyelocytic leukemia HL-60 cells are resistant to Fas-mediated apoptosis. The signaling pathway for Fas-mediated apoptosis in various cells, including HL-60 cells, is currently unknown. Here, we studied the role of survival/apoptosis associated phosphatidylinositol 3-kinase (PI 3-K)/Akt in this process. We found that both PI 3-K inhibitors, wortmannin and LY294002, markedly suppressed phosphorylation of Akt and Bad in HL-60 cells. PI 3-K inhibitors significantly accelerated not only spontaneous apoptosis, but also Fas-induced apoptosis in HL-60 cells. The pro-apoptotic effect of PI 3-K inhibitors favored Fas-mediated apoptosis rather than spontaneous apoptosis in HL-60 cells. The caspase-3 or -8 inhibitor reduced the pro-apoptotic effect of the PI 3-K inhibitors for Fas-mediated apoptosis in HL-60 cells, but the caspase-9 inhibitor did not. Although PI 3-K inhibitors did not affect Fas expression in HL-60 cells, cellular FLICE-inhibitory protein (c-FLIP) levels were markedly reduced by PI 3-K inhibitor treatment. Furthermore, antisense oligonucleotide of c-FLIP confirmed that down-regulation of c-FLIP enhanced sensitization to Fas-mediated apoptosis in HL-60 cells. These results suggest that the PI 3-K/Akt signaling pathway may, in part, regulate Fas-mediated apoptosis in HL-60 cells through c-FLIP expression.

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November 2005
Volume 14 Issue 5

Print ISSN: 1021-335X
Online ISSN:1791-2431

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Spandidos Publications style
Kondo G, Iwase M, Watanabe H, Uchida M, Takaoka S, Ohashi M, Ito D and Nagumo M: Enhancement of susceptibility to Fas-mediated apoptosis in HL-60 cells through down-regulation of cellular FLICE-inhibitory protein by phosphatidylinositol 3-kinase inhibitors. Oncol Rep 14: 1215-1222, 2005
APA
Kondo, G., Iwase, M., Watanabe, H., Uchida, M., Takaoka, S., Ohashi, M. ... Nagumo, M. (2005). Enhancement of susceptibility to Fas-mediated apoptosis in HL-60 cells through down-regulation of cellular FLICE-inhibitory protein by phosphatidylinositol 3-kinase inhibitors. Oncology Reports, 14, 1215-1222. https://doi.org/10.3892/or.14.5.1215
MLA
Kondo, G., Iwase, M., Watanabe, H., Uchida, M., Takaoka, S., Ohashi, M., Ito, D., Nagumo, M."Enhancement of susceptibility to Fas-mediated apoptosis in HL-60 cells through down-regulation of cellular FLICE-inhibitory protein by phosphatidylinositol 3-kinase inhibitors". Oncology Reports 14.5 (2005): 1215-1222.
Chicago
Kondo, G., Iwase, M., Watanabe, H., Uchida, M., Takaoka, S., Ohashi, M., Ito, D., Nagumo, M."Enhancement of susceptibility to Fas-mediated apoptosis in HL-60 cells through down-regulation of cellular FLICE-inhibitory protein by phosphatidylinositol 3-kinase inhibitors". Oncology Reports 14, no. 5 (2005): 1215-1222. https://doi.org/10.3892/or.14.5.1215