Survival of human multiple myeloma cells is dependent on MUC1 C-terminal transmembrane subunit oncoprotein function.
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.
Yin
Li
L
Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115-6084, USA.
Ahmad
Rehan
R
Kosugi
Michio
M
Kufe
Turner
T
Vasir
Baldev
B
Avigan
David
D
Kharbanda
Surender
S
Kufe
Donald
D
D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000737:chemistry / Q000502:physiology*; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D016328:NF-kappa B / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014183:Transplantation, Heterologous
D018396:Mucin-1; D016328:NF-kappa B; D017382:Reactive Oxygen Species
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