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
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
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DOI：
10.1038/onc.2009.214
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发表时间：
2009-10-08
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影响因子：
8
通讯作者：
Bonavida, B.
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文献类型：
--
作者：
Baritaki, S.;Chapman, A.;Bonavida, B.
转移与上皮特征的丧失以及肿瘤细胞获得间质特征和侵袭特性相关，这一过程称为上皮向间质转化（EMT）。通过核因子（NF）-κ B活化的Snail表达是EMT决定因子。蛋白酶体抑制剂NPI-0052通过NF-κ B抑制作用诱导转移肿瘤抑制/免疫监视癌症基因Raf激酶抑制蛋白（RKIP）。我们假设NPI-0052可以抑制Snail表达，并因此抑制DU-145前列腺癌细胞中的转移表型。用NPI-0052处理细胞诱导E-钙粘蛋白并抑制Snail表达以及肿瘤细胞侵袭和迁移。Snail的抑制与RKIP的诱导呈负相关。NPI-0052诱导的转移表型抑制的潜在机制通过以下方式证实：（1）在DU-145中用Snail siRNA处理抑制EMT，相反，在非转移性LNCaP细胞中过表达Snail诱导EMT，（2）特异性NF-κ B抑制剂DHMEQ证实了NPI-0052通过抑制NF-κ B诱导的Snail阻遏，以及（3）RKIP过表达模拟NPI-0052对Snail和EMT的抑制。这些发现首次证明了NPI-0052通过抑制NF-κ B和Snail以及诱导RKIP在EMT调节中的作用。Oncogene（2009）28，3573-3585; doi：10.1038/onc.2009.214; 2009年7月27日在线发表
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