Enhanced susceptibility to tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in oral squamous cell carcinoma cells treated with phosphatidylinositol 3-kinase inhibitors

  • Authors:
    • Makiko Uchida
    • Masayasu Iwase
    • Sayaka Takaoka
    • Sayaka Yoshiba
    • Gen Kondo
    • Hitoshi Watanabe
    • Masaru Ohashi
    • Masao Nagumo
    • Satoru Shintani
  • View Affiliations

  • Published online on: May 1, 2007     https://doi.org/10.3892/ijo.30.5.1163
  • Pages: 1163-1171
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Abstract

In general, oral squamous cell carcinoma (OSCC) cells are relatively resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis during culture in vitro. Here, we studied the role of phosphatidylinositol 3-kinase (PI 3-K)/Akt in survival and apoptosis of these cells. The PI 3-K inhibitors wortmannin and LY294002 markedly suppressed phosphorylation of Akt and accelerated TRAIL-mediated apoptosis in OSCC cells. Addition of TRAIL to PI 3-K inhibitor-treated cells resulted in caspase-8 activation and loss of mitochondrial membrane potential. Furthermore, inhibitors of caspase-3, -8 and -9 reduced the accelerative effect of PI 3-K inhibitors on TRAIL-mediated apoptosis. These results suggest that the pro-apoptotic effect of PI 3-K inhibitors on TRAIL-mediated apoptosis may contribute to both the extrinsic and intrinsic pathways. Although PI 3-K inhibitors did not affect expression of the TRAIL receptors DR4 and DR5, we observed a marked reduction in expression of cellular FLICE-inhibitory protein (c-FLIP), Bcl-2, cellular inhibitor of apoptosis protein-1 (cIAP-1) and X-linked IAP (XIAP), whereas Bax was up-regulated and no significant difference was observed in expression of Bcl-xL, Bak or cIAP-2. Therefore, the PI 3-K/Akt signaling pathway provides partial regulation of TRAIL-mediated apoptosis in OSCC cells via modulation of c-FLIP, Bcl-2, Bax, cIAP-1 and XIAP expression. These results suggest that PI 3-K inhibitors may represent a novel strategy for overcoming resistance to TRAIL-mediated apoptosis in OSCC cells.

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May 2007
Volume 30 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Uchida M, Iwase M, Takaoka S, Yoshiba S, Kondo G, Watanabe H, Ohashi M, Nagumo M and Shintani S: Enhanced susceptibility to tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in oral squamous cell carcinoma cells treated with phosphatidylinositol 3-kinase inhibitors. Int J Oncol 30: 1163-1171, 2007
APA
Uchida, M., Iwase, M., Takaoka, S., Yoshiba, S., Kondo, G., Watanabe, H. ... Shintani, S. (2007). Enhanced susceptibility to tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in oral squamous cell carcinoma cells treated with phosphatidylinositol 3-kinase inhibitors. International Journal of Oncology, 30, 1163-1171. https://doi.org/10.3892/ijo.30.5.1163
MLA
Uchida, M., Iwase, M., Takaoka, S., Yoshiba, S., Kondo, G., Watanabe, H., Ohashi, M., Nagumo, M., Shintani, S."Enhanced susceptibility to tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in oral squamous cell carcinoma cells treated with phosphatidylinositol 3-kinase inhibitors". International Journal of Oncology 30.5 (2007): 1163-1171.
Chicago
Uchida, M., Iwase, M., Takaoka, S., Yoshiba, S., Kondo, G., Watanabe, H., Ohashi, M., Nagumo, M., Shintani, S."Enhanced susceptibility to tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in oral squamous cell carcinoma cells treated with phosphatidylinositol 3-kinase inhibitors". International Journal of Oncology 30, no. 5 (2007): 1163-1171. https://doi.org/10.3892/ijo.30.5.1163