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Bortezomib represses HIF-1α protein expression and nuclear accumulation by inhibiting both PI3K/Akt/TOR and MAPK pathways in prostate cancer cells

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An Erratum to this article was published on 17 April 2013

Abstract

Bortezomib represents the first proteasome inhibitor (PI) with demonstrated antitumor activity in the clinical setting, particularly for treatment of hematological malignancies. At the preclinical level, its action is shown to be mediated by induction of growth arrest and apoptosis in many tumor types, including androgen-dependent (AD) and androgen-independent (AI) prostate cancer (PCa) cells. Hypoxia-inducible factor-1α (HIF-1α), which is directly involved in tumor growth, is one of the most studied and promising molecular targets for anti-cancer therapy and is often overexpressed in PCa. Bortezomib has been reported to impair tumor growth by also inhibiting HIF-1α. In this study, we investigated the effect of bortezomib on the expression, activity and localization of HIF-1α in LNCaP (AD) and PC3 (AI) PCa cells. First, we show that hypoxic upregulation of HIF-1α protein levels and activity involves both the PI3K/Akt/mTOR and p44/42 MAPK pathways. Second, bortezomib inhibits expression of HIF-1α protein under both normoxic and hypoxic conditions, represses HIF-1 transcriptional activity and attenuates the release of vascular endothelial growth factor. These effects correlate with the ability of bortezomib to cause dephosphorylation of phospho-Akt, phospho-p70S6K, and phospho-S6RP, thus inactivating a pathway known to be required for HIF-1α protein expression at the translational level. Furthermore, bortezomib also abrogates p44/42 MAPK phosphorylation, which results to reduced nuclear translocation of HIF-1α. Taken together, these results suggest that bortezomib inhibits HIF-1α protein synthesis and its nuclear targeting through suppression of PI3K/Akt/mTOR and MAPK pathways, respectively, in both AD and AI PCa cells.

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Acknowledgments

We would wish to thank Dr. A. J. Giaccia (Stanford University) and Dr. M. U. Muckenthaler (University of Heidelberg, Germany) for providing us with the firefly luciferase reporter plasmid pGL3–5HRE-VEGF and the Renilla luciferase expressing plasmid PCIRenilla, respectively. We also thank Professor A. Molyvdas and Dr E. Paraskeva (Department of Physiology, University of Thessaly School of Medicine, Biopolis, Larissa, Greece) for use of research equipments in their laboratories.

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The authors report no potential conflict of interest relevant to this article.

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Authors and Affiliations

  1. Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Biopolis, 41110, Larissa, Greece

    Christina D. Befani, Sophia Bonanou, George Simos & Panagiotis Liakos

  2. Department of Medical Oncology, University Hospital of Larissa, University of Thessaly, Biopolis, 41110, Larissa, Greece

    Panagiotis J. Vlachostergios, Eleana Hatzidaki, Anna Patrikidou & Christos N. Papandreou

  3. Institute of Biomedical Research and Technology (BIOMED), 51 Papanastasiou str, 41222, Larissa, Greece

    George Simos & Panagiotis Liakos

  4. Faculty of Medicine, Laboratory of Biochemistry, University of Thessaly, Biopolis, 41110, Larissa, Greece

    Panagiotis Liakos

  5. Department of Medical Oncology, Faculty of Medicine, University Hospital of Larissa, University of Thessaly, Biopolis, 41110, Larissa, Greece

    Christos N. Papandreou

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  1. Christina D. Befani
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  2. Panagiotis J. Vlachostergios
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  6. George Simos
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  7. Christos N. Papandreou
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Correspondence to Christos N. Papandreou or Panagiotis Liakos.

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C. N. Papandreou and P. Liakos have equal contributions.

An erratum to this article is available at http://dx.doi.org/10.1007/s00109-013-1030-4.

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Befani, C.D., Vlachostergios, P.J., Hatzidaki, E. et al. Bortezomib represses HIF-1α protein expression and nuclear accumulation by inhibiting both PI3K/Akt/TOR and MAPK pathways in prostate cancer cells. J Mol Med 90, 45–54 (2012). https://doi.org/10.1007/s00109-011-0805-8

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  • DOI: https://doi.org/10.1007/s00109-011-0805-8

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