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Blockade of ubiquitin-conjugating enzyme CDC34 enhances anti-myeloma activity of Bortezomib/Proteasome inhibitor PS-341

Oncogene volume 23, pages 3597–3602 (2004)Cite this article

Abstract

The ubiquitin-conjugating enzyme CDC34 (UBC3) is linked to cell cycle progression in diverse cell types; however, its role in multiple myeloma (MM) pathogenesis is unclear. Here, we show that CDC34 is highly expressed in patient MM cells and MM cell lines versus normal cells. Blocking CDC34 using a dominant-negative strategy enhances the anti-MM activity of Bortezomib/Proteasome inhibitor PS-341, dexamethasone (Dex) and 2-Methoxyestradiol (2ME2). The expression of wild-type CDC34 reduces Dex-induced cytotoxicity in MM cells. Moreover, inhibition of CDC34 enzymatic activity abrogates interleukin-6-induced protection against Dex-induced apoptosis. Together, these findings provide evidence that (1) CDC34 expression is associated with growth and survival of MM cells and (2) blocking CDC34 activity not only enhances anti-MM activity of Bortezomib and 2ME2 but also overcomes IL-6-triggered Dex-resistance.

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Abbreviations

MM:

multiple myeloma

2ME2:

2-Methoxyestradiol

Dex:

dexamethasone

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Acknowledgements

This investigation was supported by NIH Grants RO-1 CA 50947, PO-1 CA 78373, and IP50CA10070, a Doris Duke Distinguished Clinical Research Scientist Award (KCA), The Myeloma Research Fund, and The Cure Myeloma Fund.

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Authors and Affiliations

  1. Department of Medical Oncology, Harvard Medical School, The Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute, 44 Binney Street, Boston, 02115, MA, USA

    Dharminder Chauhan, Guilan Li, Teru Hideshima, Klaus Podar, Reshma Shringarpure, Constantine Mitsiades, Nikhil Munshi & Kenneth C Anderson

  2. Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, 78245-3207, TX, USA

    P Renee Yew

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  1. Dharminder Chauhan
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  2. Guilan Li
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  9. Kenneth C Anderson
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Correspondence to Kenneth C Anderson.

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Chauhan, D., Li, G., Hideshima, T. et al. Blockade of ubiquitin-conjugating enzyme CDC34 enhances anti-myeloma activity of Bortezomib/Proteasome inhibitor PS-341. Oncogene 23, 3597–3602 (2004). https://doi.org/10.1038/sj.onc.1207458

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