RT Journal Article
SR Electronic
T1 SURVIVAL OF HUMAN MULTIPLE MYELOMA CELLS IS DEPENDENT ON MUC1-C ONCOPROTEIN FUNCTION
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.110.065011
DO 10.1124/mol.110.065011
A1 Li Yin
A1 Rehan Ahmad
A1 Michio Kosugi
A1 Turner Kufe
A1 Baldev Vasir
A1 David Avigan
A1 Surender Kharbanda
A1 Donald Kufe
YR 2010
UL http://molpharm.aspetjournals.org/content/early/2010/05/05/mol.110.065011.abstract
AB The MUC1-C oncoprotein is a direct activator of the canonical NF-κB RelA/p65 pathway and is aberrantly expressed in human multiple myeloma cells. However, it is not known if multiple myeloma cells are sensitive to 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 (i) the interaction between MUC1-C and NF-κB p65 and (ii) 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.The American Society for Pharmacology and Experimental Therapeutics