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Combined inhibition of extracellular signal-regulated kinases and HSP90 sensitizes human colon carcinoma cells to ionizing radiation

Oncogene volume 24, pages 3011–3019 (2005)Cite this article

Abstract

Indomethacin, a common nonsteroidal anti-inflammatory drug, has been shown to enhance radiation-mediated cell-killing effect through the activation of p38 mitogen-activated protein kinase (MAPK). We found that indomethacin strongly reduced the basal level of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in HT-29 human colon carcinoma cells. The inhibition of ERK1/2 by indomethacin was only observed in cells with high basal activities of ERK1/2 such as HT-29 cells, but not in cells with low basal activities, such as HeLa. Cell cycle analysis of HT-29 cells exposed with indomethacin showed a partial G1/S arrest and slow DNA synthesis. However, the treatment with NS398, a specific COX-1/2 inhibitor, failed to show any effect on cell cycle, indicating that the inhibition of COX-1/2 is not responsible for cell cycle arrest. Since U0126, a specific inhibitor for MEK1/2, also induced a partial G1/S arrest, the G1/S arrest induced by indomethacin is, at least in part, caused by the inhibition of ERK1/2. Cell proliferation of HT-29 was inhibited by the treatment of U0126 but not in HeLa cells, and the treatment of HT-29 cells with U0126 enhanced radiation sensitivity possibly due to the accumulation of cells in G1 phase. We found that 17-allylamino-17-demethoxygeldanamycin, a geldanamycin delivative, radiosensitized HT-29 cells at a relatively low dose of irradiation, and indomethacin and U0126 further enhanced this effect. Therefore, tumor cells with elevated ERK1/2 activity can be effectively sensitized to radiation treatment by a combinational inhibition of HSP90 and MAPK activity.

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Abbreviations

NSAID:

nonsteroidal anti-inflammatory drug

ERK:

extracellular signal-regulated kinase

COX:

cyclooxygenase

MAPK:

mitogen-activated protein kinase

MEK:

MAPK/ERK kinase

IR:

ionizing radiation

IMRT:

intensity-modulated radiation therapy

JNK:

Jun amino-terminal kinase

TGF:

transforming growth factor

EGF:

epidermal growth factor

EGFR:

epidermal growth factor receptor

BrdU:

bromodeoxyuridine

PI3K:

phosphatidylinositol 3-kinase

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Acknowledgements

We thank Drs David Gius and Michael Freeman for providing the materials used in this study. We thank Dr Hisashi Kurosawa for his generous support. We also thank Nicholle Johnson for her technical assistance. This work was supported by the Department of Radiation Oncology, Washington University School of Medicine, American Cancer Society RPG0029201, National Institute of Health P01CA104457, and R01CA98666 to NH.

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Author notes

  1. Shinichiro Kobayashi

    Present address: Department of Orthopedic Surgery, Juntendo University, Tokyo, Japan

  2. Shinichiro Kobayashi and Regan Nantz: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Radiation Oncology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, 63108, USA

    Shinichiro Kobayashi, Regan Nantz, Tetsuya Kitamura, Ryuji Higashikubo & Nobuo Horikoshi

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Correspondence to Nobuo Horikoshi.

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Kobayashi, S., Nantz, R., Kitamura, T. et al. Combined inhibition of extracellular signal-regulated kinases and HSP90 sensitizes human colon carcinoma cells to ionizing radiation. Oncogene 24, 3011–3019 (2005). https://doi.org/10.1038/sj.onc.1208508

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