Suppression of expression of heat shock protein 70 by gefitinib and its contribution to pulmonary fibrosis

Takushi Namba, Ken Ichiro Tanaka, Tatsuya Hoshino, Arata Azuma, Tohru Mizushima

研究成果: Article

34 引用 (Scopus)

抄録

Drug-induced interstitial lung disease (ILD), particularly pulmonary fibrosis, is of serious clinical concern. Gefitinib, a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), is beneficial as a drug for treating non-small cell lung cancer; however, this drug induces ILD and the molecular mechanisms underpinning this condition remain unclear. We recently reported that expression of heat shock protein 70 (HSP70) protects against bleomycin-induced pulmonary fibrosis, an animal model of pulmonary fibrosis. In this study, we have examined the effects of drugs known to induce ILD clinically on the expression of HSP70 in cultured lung epithelial cells and have found that gefitinib has a suppressive effect. Results of a luciferase reporter assay, pulse-labelling analysis of protein and experiments using an inhibitor of translation or transcription suggest that gefitinib suppresses the expression of HSP70 at the level of translation. Furthermore, the results of experiments with siRNA for Dicer1, an enzyme responsible for synthesis of microRNA, and real-time RT-PCR analysis suggest that some microRNAs are involved in the gefitinib-induced translational inhibition of HSP70. Mutations in the EGFR affect the concentration of gefitinib required for suppressing the expression of HSP70. These results suggest that gefitinib suppresses the translation of HSP70 through an EGFR- and microRNA-mediated mechanism. In vivo, while oral administration of gefitinib suppressed the pulmonary expression of HSP70 and exacerbated bleomycin-induced pulmonary fibrosis in wild-type mice, these effects were not as distinct in transgenic mice expressing HSP70. Furthermore, oral co-administration of geranylgeranylacetone (GGA), an inducer of HSP70, suppressed gefitinib-induced exacerbation of bleomycin-induced pulmonary fibrosis. Taken together, these findings suggest that gefitinib-induced exacerbation of bleomycin-induced pulmonary fibrosis is mediated by suppression of pulmonary expression of HSP70 and that an inducer of HSP70 expression, such as GGA, may be therapeutically beneficial for the treatment of gefitinib-induced pulmonary fibrosis.

元の言語English
記事番号e27296
ジャーナルPLoS One
6
発行部数11
DOI
出版物ステータスPublished - 2011 11 9
外部発表Yes

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HSP70 Heat-Shock Proteins
Pulmonary Fibrosis
fibrosis
lungs
geranylgeranylacetone
Bleomycin
Pulmonary diseases
Interstitial Lung Diseases
MicroRNAs
microRNA
Epidermal Growth Factor Receptor
respiratory tract diseases
translation (genetics)
drugs
Pharmaceutical Preparations
Lung
Oral Administration
gefitinib
heat-shock protein 70
mice

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

これを引用

Suppression of expression of heat shock protein 70 by gefitinib and its contribution to pulmonary fibrosis. / Namba, Takushi; Tanaka, Ken Ichiro; Hoshino, Tatsuya; Azuma, Arata; Mizushima, Tohru.

:: PLoS One, 巻 6, 番号 11, e27296, 09.11.2011.

研究成果: Article

Namba, Takushi ; Tanaka, Ken Ichiro ; Hoshino, Tatsuya ; Azuma, Arata ; Mizushima, Tohru. / Suppression of expression of heat shock protein 70 by gefitinib and its contribution to pulmonary fibrosis. :: PLoS One. 2011 ; 巻 6, 番号 11.
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