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Nmi (N‐Myc interactor) inhibits Wnt/β‐catenin signaling and retards tumor growth
Author(s) -
Fillmore Rebecca A.,
Mitra Aparna,
Xi Yaguang,
Ju Jingfang,
Scammell Jonathan,
Shevde Lalita A.,
Samant Rajeev S.
Publication year - 2009
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.24276
Subject(s) - dkk1 , wnt signaling pathway , mg132 , biology , cancer research , cell growth , cell culture , transcription factor , signal transduction , catenin , beta catenin , microbiology and biotechnology , proteasome inhibitor , biochemistry , gene , genetics
We found that the expression levels of N‐Myc interactor (Nmi) were low in aggressive breast cancer cell lines when compared with less aggressive cell lines. However, the lower levels in the aggressive lines were inducible by interferon‐γ (IFN‐γ). Because Nmi has been reported to be a transcription cofactor that augments IFN‐γ induced transcription activity, we decided to test whether Nmi regulates expression of Dkk1, which is also inducible by IFN‐γ. We established stable clones constitutively expressing Nmi in MDA‐MB‐231 (breast) and MDA‐MB‐435 (melanoma) cell lines. Dkk1 was significantly up‐regulated in the Nmi expressing clones concurrent with reduced levels of the critical transcription cofactor of Wnt pathway, β‐catenin. Treatment of the Nmi expressors with blocking antibody to Dkk1 restored β‐catenin protein levels. c‐Myc is a known downstream target of activated β‐catenin signaling. Treatment of Nmi expressors with the proteosome inhibitor MG132, resulted in elevated β‐catenin levels with concomitant elevation of c‐Myc levels. Our functional studies showed that constitutive expression of Nmi reduced the ability of tumor cells for the invasion, anchorage independent growth and tumor growth in vivo . Collectively, the data suggest that overexpression of Nmi inhibits the Wnt/β‐catenin signaling via up‐regulation of Dkk1 and retards tumor growth. © 2009 UICC