Baritaki S, Chapman A, Yeung K, Spandidos D A, Palladino M, Bonavida B
Department of Microbiology, Immunology and Molecular Genetics, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095-736422, USA.
Oncogene. 2009 Oct 8;28(40):3573-85. doi: 10.1038/onc.2009.214. Epub 2009 Jul 27.
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.
转移与肿瘤细胞上皮特征的丧失以及间充质特征和侵袭特性的获得相关，这一过程称为上皮-间充质转化（EMT）。通过核因子（NF）-κB激活，Snail表达是EMT的一个决定因素。蛋白酶体抑制剂NPI-0052通过抑制NF-κB诱导转移肿瘤抑制因子/免疫监视癌症基因——Raf激酶抑制蛋白（RKIP）。我们假设NPI-0052可能抑制Snail表达，从而抑制DU-145前列腺癌细胞的转移表型。用NPI-0052处理细胞可诱导E-钙黏蛋白表达，抑制Snail表达以及肿瘤细胞的侵袭和迁移。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得到以下方面的证实：（1）在DU-145细胞中用Snail小干扰RNA（siRNA）处理可抑制EMT，相反，在非转移性LNCaP细胞中过表达Snail可诱导EMT；（2）特异性NF-κB抑制剂DHMEQ证实了NPI-0052通过抑制NF-κB对Snail的抑制作用；（3）RKIP过表达在抑制Snail和EMT方面模拟了NPI-0052的作用。这些发现首次证明了NPI-0052通过抑制NF-κB和Snail以及诱导RKIP在EMT调控中的作用。
