Inhibition of PI3 kinases enhances the sensitivity of non-small cell lung cancer cells to ionizing radiation

  • Authors:
    • Tao Zhang
    • Guang-Bin Cui
    • Jian Zhang
    • Feng Zhang
    • Yong-An Zhou
    • Tao Jiang
    • Xiao-Fei Li
  • View Affiliations

  • Published online on: December 1, 2010     https://doi.org/10.3892/or_00001034
  • Pages: 1683-1689
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Abstract

Non-small cell lung cancer (NSCLC) cells are relatively resistant to ionizing radiation (IR). The phosphatidylinositol 3 (PI3) kinases are members of a family of lipid kinases that mediate cellular functions, including cell growth, proliferation and DNA repair, which may contribute to radioresistance. We studied whether inhibition of PI3 kinases could increase the response of NSCLC cells to γ-irradiation. The results showed that pretreatment of PI3 kinase inhibitor wortmannin dose-dependently radiosensitized NSCLC A549 and H1650 cells by inhibiting colony formation, which was due to enhanced G2/M arrest and apoptosis by wortmannin. The accelerated apoptosis was accompanied by increased loss of mitochondrial membrane potential (MMP) and cytochrome c release to the cytoplasm. In addition, wortmannin pretreatment significantly increased caspase-3 activation, which was associated with the repression of X-linked inhibitor of apoptosis protein (XIAP). The radio-sensitizing effect of wortmannin was correlated with the inhibition of phosphorylated PKB/Akt level. Furthermore, wortmannin down-regulated the expression of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) which is involved in DNA double stand break (DSB) repair, as a result, leading to the inhibition of DSBs rejoining, as indicated by increased level of γ-H2AX at 24 h after IR. Taken together, our results demonstrate that wortmannin acts as a powerful radiosensitizer in NSCLC cells by inhibiting PI3K/Akt survival signaling and DNA repair protein DNA-PKcs, suggesting that PI3 kinase inhibitors may represent a novel strategy for overcoming resistance to IR-induced apoptosis in NSCLC cells.

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December 2010
Volume 24 Issue 6

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

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Spandidos Publications style
Zhang T, Cui G, Zhang J, Zhang F, Zhou Y, Jiang T and Li X: Inhibition of PI3 kinases enhances the sensitivity of non-small cell lung cancer cells to ionizing radiation . Oncol Rep 24: 1683-1689, 2010
APA
Zhang, T., Cui, G., Zhang, J., Zhang, F., Zhou, Y., Jiang, T., & Li, X. (2010). Inhibition of PI3 kinases enhances the sensitivity of non-small cell lung cancer cells to ionizing radiation . Oncology Reports, 24, 1683-1689. https://doi.org/10.3892/or_00001034
MLA
Zhang, T., Cui, G., Zhang, J., Zhang, F., Zhou, Y., Jiang, T., Li, X."Inhibition of PI3 kinases enhances the sensitivity of non-small cell lung cancer cells to ionizing radiation ". Oncology Reports 24.6 (2010): 1683-1689.
Chicago
Zhang, T., Cui, G., Zhang, J., Zhang, F., Zhou, Y., Jiang, T., Li, X."Inhibition of PI3 kinases enhances the sensitivity of non-small cell lung cancer cells to ionizing radiation ". Oncology Reports 24, no. 6 (2010): 1683-1689. https://doi.org/10.3892/or_00001034