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
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The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
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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].
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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.
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
doi:10.1124/mol.110.065011.
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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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