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Translational suppression of HIF-1α by miconazole through the mTOR signaling pathway

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Abstract

Background

Miconazole is an imidazole antifungal agent that has amply been used in the treatment of superficial mycosis. Preliminary data indicate that miconazole may also induce anticancer effects. As yet, however, little is known about the therapeutic efficacy of miconazole on cancer and the putative mechanism(s) involved. Here, we show that miconazole suppresses hypoxia inducible factor-1α (HIF-1α) protein translation in different cancer-derived cells.

Methods

The effect of miconazole on HIF-1α expression was examined by Western blotting and reverse transcriptase polymerase chain reaction assays in human U87MG and MCF-7 glioma and breast cancer-derived cell lines, respectively. The transcriptional activity of the HIF-1 complex was confirmed using a luciferase assay. To assess whether angiogenic factors are increased under hypoxic conditions in these cells, vascular endothelial growth factor (VEGF) levels were measured by ELISA. Metabolic labeling was performed to examine HIF-1α protein translation and global protein synthesis. The role of the mammalian target of rapamycin (mTOR) signaling pathway was examined to determine translation regulation of HIF-1α after miconazole treatment.

Results

Miconazole was found to suppress HIF-1α protein expression through post-transcriptional regulation in U87MG and MCF-7 cells. The suppressive effect of HIF-1α protein synthesis was found to be due to inhibition of mTOR. Miconazole significantly inhibited the transcriptional activity of the HIF-1 complex and the expression of its target VEGF. Moreover, miconazole was found to suppress global protein synthesis by inducing phosphorylation of the translation initiation factor 2α (eIF2α).

Conclusion

Our data indicate that miconazole plays a role in translational suppression of HIF-1α. We suggest that miconazole may represent a novel therapeutic option for the treatment of cancer.

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Acknowledgments

We would like to thank Dr. Giovanni Melillo (National Cancer Institute, Frederick, MD, USA) for providing the pGL2-TK-HRE plasmid. This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science and Technology (NRF-2011-0013913).

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All authors of this manuscript declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Microbiology, Keimyung University School of Medicine, 1095 Dalgubeol-daero, Dalseo-gu, Daegu, 704-701, Republic of Korea

    Jee-Young Park, Hui-Jung Jung, Incheol Seo, Bijay Kumar Jha, Seong-Il Suh, Min-Ho Suh & Won-Ki Baek

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  1. Jee-Young Park
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Correspondence to Won-Ki Baek.

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Jee-Young Park and Hui-Jung Jung contributed equally to this work.

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Park, JY., Jung, HJ., Seo, I. et al. Translational suppression of HIF-1α by miconazole through the mTOR signaling pathway. Cell Oncol. 37, 269–279 (2014). https://doi.org/10.1007/s13402-014-0182-8

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