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细胞内递送源自 PIAS3 酸性结构域的重组肽抑制 STAT3 反式激活并诱导肿瘤细胞死亡。

The intracellular delivery of a recombinant peptide derived from the acidic domain of PIAS3 inhibits STAT3 transactivation and induces tumor cell death.

机构信息

Institute for Biomedical Research, Georg-Speyer-Haus, Frankfurt am Main, Germany.

出版信息

Mol Cancer Res. 2010 Apr;8(4):539-53. doi: 10.1158/1541-7786.MCR-09-0417. Epub 2010 Apr 6.

Abstract

Signaling components, which confer an "addiction" phenotype on cancer cells, represent promising drug targets. The transcription factor signal transducers and activators of transcription 3 (STAT3) is constitutively activated in many different types of tumor cells and its activity is indispensible in a large fraction. We found that the expression of the endogenous inhibitor of STAT3, protein inhibitor of activated STAT3 (PIAS3), positively correlates with STAT3 activation in normal cells. This suggests that PIAS3 controls the extent and the duration of STAT3 activity in normal cells and thus prevents its oncogenic function. In cancer cells, however, the expression of PIAS3 is posttranscriptionally suppressed, possibly enhancing the oncogenic effects of activated STAT3. We delimited the interacting domains of STAT3 and PIAS3 and identified a short fragment of the COOH-terminal acidic region of PIAS3, which binds strongly to the coiled-coil domain of STAT3. This PIAS3 fragment was used to derive the recombinant STAT3-specific inhibitor rPP-C8. The addition of a protein transduction domain allowed the efficient internalization of rPP-C8 into cancer cells. This resulted in the suppression of STAT3 target gene expression, in the inhibition of migration and proliferation, and in the induction of apoptosis at low concentrations [half maximal effective concentration (EC(50)), <3 micromol/L]. rPP-C8 did not affect normal fibroblasts and represents an interesting lead for the development of novel cancer drugs targeting the coiled-coil domain of STAT3.

摘要

信号转导组件使癌细胞具有“成瘾”表型,成为有前途的药物靶点。转录因子信号转导子和转录激活子 3(STAT3)在许多不同类型的肿瘤细胞中持续激活,其活性在很大一部分肿瘤细胞中是必不可少的。我们发现,STAT3 的内源性抑制剂蛋白激活 STAT3 抑制剂 3(PIAS3)的表达与正常细胞中 STAT3 的激活呈正相关。这表明 PIAS3 控制正常细胞中 STAT3 活性的程度和持续时间,从而防止其致癌功能。然而,在癌细胞中,PIAS3 的表达被转录后抑制,可能增强了激活的 STAT3 的致癌作用。我们限定了 STAT3 和 PIAS3 的相互作用域,并鉴定了 PIAS3 的羧基末端酸性区的一个短片段,该片段与 STAT3 的卷曲螺旋域强烈结合。该 PIAS3 片段被用来衍生重组 STAT3 特异性抑制剂 rPP-C8。添加蛋白转导结构域允许 rPP-C8 有效地内化进入癌细胞。这导致 STAT3 靶基因表达的抑制、迁移和增殖的抑制以及低浓度(半最大有效浓度(EC(50)),<3 微摩尔/L)下的凋亡诱导。rPP-C8 不影响正常成纤维细胞,是针对 STAT3 卷曲螺旋域开发新型癌症药物的一个有趣的先导。

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