Inhibition of epithelial to mesenchymal transition in metastatic prostate cancer cells by the novel proteasome inhibitor, NPI-0052: pivotal roles of Snail repression and RKIP induction

被引：122

作者：

Baritaki, S. ^{[1
]}

Chapman, A. ^{[1
]}

Yeung, K. ^{[2
]}

Spandidos, D. A. ^{[3
]}

Palladino, M. ^{[4
]}

Bonavida, B. ^{[1
]}

机构：

[1] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Jonsson Comprehens Canc Ctr, David Geffen Sch Med, Los Angeles, CA 90095 USA

[2] Univ Toledo, Dept Canc Biol & Biochem, Coll Med, Toledo, OH 43606 USA

[3] Univ Crete, Fac Med, Dept Clin Virol, Iraklion, Greece

[4] Nereus Pharmaceut, San Diego, CA USA

来源：

ONCOGENE | 2009年 / 28卷 / 40期

关键词：

metastasis; epithelial to mesenchymal transition; proteasome inhibitor; NF-kappa B; Raf-1 kinase inhibitor protein; Snail; NF-KAPPA-B; RAF KINASE; E-CADHERIN; PROTEIN EXPRESSION; TRANSCRIPTION FACTORS; INDUCED APOPTOSIS; MULTIPLE-MYELOMA; TUMOR-CELLS; IN-VITRO; SUPPRESSES;

D O I：

10.1038/onc.2009.214

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Metastasis is associated with the loss of epithelial features and the acquisition of mesenchymal characteristics and invasive properties by tumor cells, a process known as epithelial to mesenchymal transition (EMT). Snail expression, through nuclear factor (NF)-kappa B activation, is an EMT determinant. The proteasome inhibitor, NPI-0052, induces the metastasis tumor suppressor/immune surveillance cancer gene, Raf kinase inhibitor protein (RKIP), via NF-kappa B inhibition. We hypothesized that NPI-0052 may inhibit Snail expression and, consequently, the metastatic phenotype in DU-145 prostate cancer cells. Cell treatment with NPI-0052 induced E-cadherin and inhibited Snail expression and both tumor cell invasion and migration. Inhibition of Snail inversely correlated with the induction of RKIP. The underlying mechanism of NPI-0052-induced inhibition of the metastatic phenotype was corroborated by: (1) treatment with Snail siRNA in DU-145 inhibited EMT and, in contrast, overexpression of Snail in the nonmetastatic LNCaP cells induced EMT, (2) NPI-0052-induced repression of Snail via inhibition of NF-kappa B was corroborated by the specific NF-kappa B inhibitor DHMEQ and (3) RKIP overexpression mimicked NPI-0052 in the inhibition of Snail and EMT. These findings demonstrate, for the first time, the role of NPI-0052 in the regulation of EMT via inhibition of NF-kappa B and Snail and induction of RKIP. Oncogene (2009) 28, 3573-3585; doi: 10.1038/onc.2009.214; published online 27 July 2009

引用

页码：3573 / 3585

页数：13

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