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

Kondo,Gen; Iwase,Masayasu; Watanabe,Hitoshi; Uchida,Makiko; Takaoka,Sayaka; Ohashi,Masaru; Ito,Daisuke; Nagumo,Masao

doi:10.3892/or.14.5.1215

November 2005 Volume 14 Issue 5

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November 2005 Volume 14 Issue 5

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Article

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 / Copyright

Affiliations: Department of Oral and Maxillofacial Surgery, Showa University School of Dentistry, 2-1-1 Kitasenzoku, Ota-ku, Tokyo 145-8515, Japan
Pages: 1215-1222
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Published online on: November 1, 2005

https://doi.org/10.3892/or.14.5.1215
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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.

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

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

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