Abstract
Bortezomib is a proteasome inhibitor that can synergize with interferon-alpha (IFN-α) to induce apoptosis in melanoma cells in vitro and inhibit tumor growth in vivo. We hypothesized that proteasome inhibition may be an effective means to sensitize melanoma cells to the direct effects of IFN-α. Pre-treatment of human melanoma cells with bortezomib led to significantly increased transcription of interferon-stimulated genes as determined by real-time PCR. Flow cytometric and immunoblot analyses indicated that the enhanced direct actions of IFN-α on melanoma cells were the result of prolonged phosphorylation of STAT1 (P-STAT1) on both the Tyrosine701 and Serine727 residues. In contrast, the enhanced IFN-α-induced P-STAT1 was not observed in peripheral blood mononuclear cells that were pre-treated with bortezomib. These data suggest that proteasome inhibition represents a mechanism to enhance the direct effects of IFN-α on melanoma cells thereby complementing its immunostimulatory properties.
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Acknowledgments
The authors thank the Ohio State University Comprehensive Cancer Center Analytical Cytometry and Nucleic Acid Shared Resources. The Harry J. Lloyd Charitable Trust, The Melanoma Research Foundation, The Valvano Foundation for Cancer Research Award (to G.B. Lesinski), National Institutes of Health (NIH) Grants CA84402, K24 CA93670 (to W.E. Carson), K22 CA134551 (to G.B. Lesinski), P30-CA16058, P01-CA95426 (to M.A. Caligiuri), and Millennium Pharmaceuticals, Inc., and Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
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Lesinski, G.B., Benninger, K., Kreiner, M. et al. Bortezomib pre-treatment prolongs interferon-alpha-induced STAT1 phosphorylation in melanoma cells. Cancer Immunol Immunother 58, 2031–2037 (2009). https://doi.org/10.1007/s00262-009-0710-y
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DOI: https://doi.org/10.1007/s00262-009-0710-y