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.