Suppression of phosphatidylinositol 3-kinase/Akt signaling pathway is a determinant of the sensitivity to a novel histone deacetylase inhibitor, FK228, in lung adenocarcinoma cells

  • Authors:
    • Masahiro Kodani
    • Tadashi Igishi
    • Shingo Matsumoto
    • Hiroki Chikumi
    • Yasushi Shigeoka
    • Hirofumi Nakanishi
    • Masato Morita
    • Kazuhito Yasuda
    • Yutaka Hitsuda
    • Eiji Shimizu
  • View Affiliations

  • Published online on: March 1, 2005     https://doi.org/10.3892/or.13.3.477
  • Pages: 477-483
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Abstract

A novel histone deacetylase inhibitor, FK228, is a promising anticancer agent and has been proposed to modulate intracellular signaling, in addition to regulating gene transcription. We evaluated the effect of this agent on Akt-mediated signaling in relation to its cytotoxic activity using lung adenocarcinoma cell lines. Based on MTT assay and the appearance of cleaved poly (ADP-ribose) polymerase (PARP), we regarded A549 and PC14 cells as relatively sensitive and resistant cell lines, respectively. In A549 cells, FK228 suppressed the phosphorylation of Akt at Ser-473 and glycogen synthase kinase-3 without affecting these protein levels, indicating inhibition of the Akt-mediated signaling pathway. On the other hand, in PC14 cells, these biochemical reactions were not detected after treatment with FK228. The combination of FK228 and a phosphatidylinositol 3-kinase (PI3K)/Akt pathway inhibitor, LY294002, was determined to be synergistically cytotoxic in PC14 cells by isobologram analysis. This synergistic effect was attributable to the enhancement of apoptosis, as judged by flow cytometric analysis, and the appearance of cleaved PARP. The combination of FK228 with UCN-01, another PI3K/Akt pathway inhibitor, also exerted a synergistic effect. We concluded that FK228 suppresses the PI3K/Akt signaling pathway in a cell-specific manner, and this effect is a determinant of sensitivity to FK228.

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March 2005
Volume 13 Issue 3

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

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Spandidos Publications style
Kodani M, Igishi T, Matsumoto S, Chikumi H, Shigeoka Y, Nakanishi H, Morita M, Yasuda K, Hitsuda Y, Shimizu E, Shimizu E, et al: Suppression of phosphatidylinositol 3-kinase/Akt signaling pathway is a determinant of the sensitivity to a novel histone deacetylase inhibitor, FK228, in lung adenocarcinoma cells. Oncol Rep 13: 477-483, 2005.
APA
Kodani, M., Igishi, T., Matsumoto, S., Chikumi, H., Shigeoka, Y., Nakanishi, H. ... Shimizu, E. (2005). Suppression of phosphatidylinositol 3-kinase/Akt signaling pathway is a determinant of the sensitivity to a novel histone deacetylase inhibitor, FK228, in lung adenocarcinoma cells. Oncology Reports, 13, 477-483. https://doi.org/10.3892/or.13.3.477
MLA
Kodani, M., Igishi, T., Matsumoto, S., Chikumi, H., Shigeoka, Y., Nakanishi, H., Morita, M., Yasuda, K., Hitsuda, Y., Shimizu, E."Suppression of phosphatidylinositol 3-kinase/Akt signaling pathway is a determinant of the sensitivity to a novel histone deacetylase inhibitor, FK228, in lung adenocarcinoma cells". Oncology Reports 13.3 (2005): 477-483.
Chicago
Kodani, M., Igishi, T., Matsumoto, S., Chikumi, H., Shigeoka, Y., Nakanishi, H., Morita, M., Yasuda, K., Hitsuda, Y., Shimizu, E."Suppression of phosphatidylinositol 3-kinase/Akt signaling pathway is a determinant of the sensitivity to a novel histone deacetylase inhibitor, FK228, in lung adenocarcinoma cells". Oncology Reports 13, no. 3 (2005): 477-483. https://doi.org/10.3892/or.13.3.477