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Research ArticleArticle

Survival of Human Multiple Myeloma Cells Is Dependent on MUC1 C-Terminal Transmembrane Subunit Oncoprotein Function

Li Yin, Rehan Ahmad, Michio Kosugi, Turner Kufe, Baldev Vasir, David Avigan, Surender Kharbanda and Donald Kufe
Molecular Pharmacology August 2010, 78 (2) 166-174; DOI: https://doi.org/10.1124/mol.110.065011
Li Yin
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Rehan Ahmad
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Michio Kosugi
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Turner Kufe
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Baldev Vasir
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David Avigan
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Surender Kharbanda
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Donald Kufe
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Abstract

The MUC1 C-terminal transmembrane subunit (MUC1-C) oncoprotein is a direct activator of the canonical nuclear factor-κB (NF-κB) RelA/p65 pathway and is aberrantly expressed in human multiple myeloma cells. However, it is not known whether multiple myeloma cells are sensitive to the disruption of MUC1-C function for survival. The present studies demonstrate that peptide inhibitors of MUC1-C oligomerization block growth of human multiple myeloma cells in vitro. Inhibition of MUC1-C function also blocked the interaction between MUC1-C and NF-κB p65 and activation of the NF-κB pathway. In addition, inhibition of MUC1-C in multiple myeloma cells was associated with activation of the intrinsic apoptotic pathway and induction of late apoptosis/necrosis. Primary multiple myeloma cells, but not normal B-cells, were also sensitive to MUC1-C inhibition. Significantly, treatment of established U266 multiple myeloma xenografts growing in nude mice with a lead candidate MUC1-C inhibitor resulted in complete tumor regression and lack of recurrence. These findings indicate that multiple myeloma cells are dependent on intact MUC1-C function for constitutive activation of the canonical NF-κB pathway and for their growth and survival.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This study was supported by the Multiple Myeloma Research Foundation; the Leukemia Lymphoma Society; and the National Institutes of Health National Cancer Institute [Grant CA42802].

  • Disclosure of potential conflicts of interest: D.K. is an equity holder of and consultant to Genus Oncology. S.K. is an employee of Genus Oncology.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.065011.

  • ABBREVIATIONS:

    NF-κB
    nuclear factor κB
    IKK
    IκB kinase
    MUC1
    mucin 1
    MUC1-C
    MUC1 C-terminal subunit
    ROS
    reactive oxygen species
    PKCδ
    protein kinase C-δ
    PARP
    poly(ADP-ribose) polymerase
    PI
    propidium iodide
    PBS
    phosphate-buffered saline
    HE
    hydroethidine
    H&E
    hematoxylin and eosin
    zVAD-FMK
    N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone.

  • Received March 23, 2010.
  • Accepted May 5, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 78 (2)
Molecular Pharmacology
Vol. 78, Issue 2
1 Aug 2010
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Research ArticleArticle

Survival of Human Multiple Myeloma Cells Is Dependent on MUC1 C-Terminal Transmembrane Subunit Oncoprotein Function

Li Yin, Rehan Ahmad, Michio Kosugi, Turner Kufe, Baldev Vasir, David Avigan, Surender Kharbanda and Donald Kufe
Molecular Pharmacology August 1, 2010, 78 (2) 166-174; DOI: https://doi.org/10.1124/mol.110.065011

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Research ArticleArticle

Survival of Human Multiple Myeloma Cells Is Dependent on MUC1 C-Terminal Transmembrane Subunit Oncoprotein Function

Li Yin, Rehan Ahmad, Michio Kosugi, Turner Kufe, Baldev Vasir, David Avigan, Surender Kharbanda and Donald Kufe
Molecular Pharmacology August 1, 2010, 78 (2) 166-174; DOI: https://doi.org/10.1124/mol.110.065011
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