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Mol Pharmacol. 2010 Aug;78(2):166-74. doi: 10.1124/mol.110.065011. Epub 2010 May 5.

Survival of human multiple myeloma cells is dependent on MUC1 C-terminal transmembrane subunit oncoprotein function.

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1
Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115-6084, USA.

Abstract

The MUC1 C-terminal transmembrane subunit (MUC1-C) oncoprotein is a direct activator of the canonical nuclear factor-kappaB (NF-kappaB) 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-kappaB p65 and activation of the NF-kappaB 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-kappaB pathway and for their growth and survival.

PMID:
20444960
PMCID:
PMC2917857
DOI:
10.1124/mol.110.065011
[Indexed for MEDLINE]
Free PMC Article
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