MUC1 oncoprotein promotes growth and survival of human multiple myeloma cells.
The MUC1 oncoprotein is aberrantly expressed in human multiple myeloma cells by mechanisms that are not understood. Moreover, the functional role of MUC1 in multiple myeloma is not known. The present studies demonstrate that the MUC1 gene locus is amplified in multiple myeloma cell lines and in primary cells from patients. The KMS28PE multiple myeloma cell line, which was found to have MUC1 gene amplification, was stably silenced for MUC1 using different siRNAs. Silencing MUC1 was associated with a decrease in nuclear beta-catenin levels, consistent with the function of MUC1 in stabilizing beta-catenin. MUC1 is also known to activate the IKKbeta-->NF-kappaB pathway and KMS28PE cells silenced for MUC1 were found to have downregulation of IKKbeta and IkappaBalpha phosphorylation, and decreased nuclear targeting of NF-kappaB p65. The results also demonstrate that MUC1: i) contributes to KMS28PE cell proliferation, and ii) protects against apoptosis and loss of self-renewal in the response to melphalan and dexamethasone. These findings indicate that MUC1 activates the beta-catenin and NF-kappaB pathways in multiple myeloma cells and contributes to their growth and survival.
Kawano
Takeshi
T
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Ahmad
Rehan
R
Nogi
Hiroko
H
Agata
Naoki
N
Anderson
Kenneth
K
Kufe
Donald
D
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D003907:Dexamethasone / Q000494:pharmacology; D005784:Gene Amplification; D006801:Humans; D008558:Melphalan / Q000494:pharmacology; D018396:Mucin-1 / Q000235:genetics / Q000502:physiology*; D009101:Multiple Myeloma / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051176:beta Catenin / Q000502:physiology
C060192:MUC1 protein, human; D018396:Mucin-1; D016328:NF-kappa B; D034741:RNA, Small Interfering; D051176:beta Catenin; D003907:Dexamethasone; D008558:Melphalan