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.
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)-kappaB 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-kappaB 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-kappaB was corroborated by the specific NF-kappaB 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-kappaB and Snail and induction of RKIP.
Baritaki
S
S
Department of Microbiology, Immunology and Molecular Genetics, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095-736422, USA.
Chapman
A
A
Yeung
K
K
Spandidos
D A
DA
Palladino
M
M
Bonavida
B
B
D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004847:Epithelial Cells / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D008297:Male; D008648:Mesoderm / Q000473:pathology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D049488:Phosphatidylethanolamine Binding Protein / Q000235:genetics / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D011758:Pyrroles / Q000494:pharmacology*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
D007783:Lactones; D016328:NF-kappa B; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011758:Pyrroles; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C475865:marizomib