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Inhibition of epithelial to mesenchymal transition in metastatic prostate cancer cells by the novel proteasome inhibitor, NPI-0052: pivotal roles of Snail repression and RKIP induction

Oncogene volume 28, pages 3573–3585 (2009)Cite this article

Abstract

Metastasis is associated with the loss of epithelial features and the acquisition of mesenchymal characteristics and invasive properties by tumor cells, a process known as epithelial to mesenchymal transition (EMT). Snail expression, through nuclear factor (NF)-κB activation, is an EMT determinant. The proteasome inhibitor, NPI-0052, induces the metastasis tumor suppressor/immune surveillance cancer gene, Raf kinase inhibitor protein (RKIP), via NF-κB inhibition. We hypothesized that NPI-0052 may inhibit Snail expression and, consequently, the metastatic phenotype in DU-145 prostate cancer cells. Cell treatment with NPI-0052 induced E-cadherin and inhibited Snail expression and both tumor cell invasion and migration. Inhibition of Snail inversely correlated with the induction of RKIP. The underlying mechanism of NPI-0052-induced inhibition of the metastatic phenotype was corroborated by: (1) treatment with Snail siRNA in DU-145 inhibited EMT and, in contrast, overexpression of Snail in the nonmetastatic LNCaP cells induced EMT, (2) NPI-0052-induced repression of Snail via inhibition of NF-κB was corroborated by the specific NF-κB inhibitor DHMEQ and (3) RKIP overexpression mimicked NPI-0052 in the inhibition of Snail and EMT. These findings demonstrate, for the first time, the role of NPI-0052 in the regulation of EMT via inhibition of NF-κB and Snail and induction of RKIP.

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Abbreviations

DHMEQ:

dehydroxymethylepoxyquinomicin

FBS:

fetal bovine serum

FITC:

fluorescein isothiocyanate

GAPDH:

glyceraldehydes-3-phosphate dehydrogenase (G-3-PDH)

NF-κB:

nuclear factor-kB

PBS:

phosphate-buffered saline

RFU:

relative fluorescence units

RPE:

R-phycoerythrin

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Acknowledgements

This study was supported in part by the NIH/NCI research supplements CA107023-02S1, CA057152-13S1 and by Bodossaki Foundation postdoctoral fellowship (SB). We thank Chau Tran, Jose A Rodriguez and Haiming Chen for their help in the migration and invasion assays and the immunofluorescence microscopy. We also thank Dr Kazuo Umezawa for providing us with the NF-κB inhibitor DHMEQ. In addition, we thank Tiffany Chin, Katherine Wu and Erica Keng for helping in the preparation of this article.

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Authors and Affiliations

  1. Department of Microbiology, Immunology and Molecular Genetics, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA

    S Baritaki, A Chapman & B Bonavida

  2. Department of Cancer Biology and Biochemistry, College of Medicine, Health Science Campus, University of Toledo, Toledo, OH, USA

    K Yeung

  3. Department of Clinical Virology, Faculty of Medicine, University of Crete, Heraklion, Greece

    D A Spandidos

  4. Nereus Pharmaceuticals, San Diego, CA, USA

    M Palladino

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  1. S Baritaki
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Correspondence to B Bonavida.

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Baritaki, S., Chapman, A., Yeung, K. et al. Inhibition of epithelial to mesenchymal transition in metastatic prostate cancer cells by the novel proteasome inhibitor, NPI-0052: pivotal roles of Snail repression and RKIP induction. Oncogene 28, 3573–3585 (2009). https://doi.org/10.1038/onc.2009.214

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