Overexpression of GRIM-19 in Cancer Cells Suppresses STAT3-Mediated Signal Transduction and Cancer Growth
Overexpression of GRIM-19 in Cancer Cells Suppresses STAT3-Mediated Signal Transduction and Cancer Growth
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DOI：
10.1158/1535-7163.mct-09-1147
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发表时间：
2010-08
影响因子：
5.7
通讯作者：
Takashi Okamoto;T. Inozume;H. Mitsui;M. Kanzaki;K. Harada;N. Shibagaki;S. Shimada
中科院分区：
文献类型：
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作者：
Takashi Okamoto;T. Inozume;H. Mitsui;M. Kanzaki;K. Harada;N. Shibagaki;S. Shimada
信号转导子和转录激活子3（STAT 3）的组成性激活在许多人和鼠癌细胞中是常见的，并且其激活导致细胞转化。据报道，STAT 3通路抑制剂可抑制癌症生长。为了研究在癌症微环境中抑制STAT 3介导的信号级联的抗肿瘤作用，使用分子靶向方法，我们专注于与类维生素A-IFN-诱导的死亡率19（GRIM-19）相关的基因。据报道，GRIM-19与STAT 3物理相互作用并抑制STAT 3依赖性信号转导。我们使用九精氨酸（R9）-蛋白转导结构域（R9-PTD）作为蛋白载体，在体外和体内诱导GRIM-19的高水平表达。我们产生了含有R9-PTD的GRIM-19融合蛋白（rR 9-GRIM 19），并成功诱导了癌细胞胞质中的过表达。对STAT 3下游分子表达的分析证实，组成性激活的STAT 3（STAT 3c）癌细胞的体外rR 9-GRIM 19处理显著降低了STAT 3依赖性转录。此外，在携带STAT 3c癌症的小鼠中瘤内注射rR 9-GRIM 19显著抑制肿瘤生长。这些结果表明，rR 9-GRIM 19的肿瘤内注射具有作为STAT 3c癌症中的新型抗癌疗法的潜力，因为它们能够抑制STAT 3介导的信号转导而没有主要的全身副作用。Mol Cancer Ther; 9（8）; 2333-43.©2010 AACR。
Constitutive activation of signal transducer and activator of transcription 3 (STAT3) is common in many human and murine cancer cells, and its activation leads to cellular transformation. STAT3 pathway inhibitors have been reported to suppress cancer growth. To investigate the antitumor effects of inhibiting the STAT3-mediated signaling cascade in the cancer microenvironment, using a molecular-targeting approach, we focused on the gene associated with retinoid-IFN-induced mortality 19 (GRIM-19). GRIM-19 has been reported to interact physically with STAT3 and inhibit STAT3-dependent signal transduction. We used the nona-arginine (R9)-protein transduction domain (R9-PTD) as a protein carrier to induce high levels of GRIM-19 expression in vitro and in vivo. We generated an R9-PTD–containing GRIM-19 fusion protein (rR9-GRIM19) and successfully induced overexpression in the cytoplasm of cancer cells. Analysis of the expression of downstream molecules of STAT3 confirmed that in vitro rR9-GRIM19 treatment of constitutively activated STAT3 (STAT3c) cancer cells significantly reduced STAT3-dependent transcription. Moreover, intratumoral injections of rR9-GRIM19 in STAT3c cancer-bearing mice significantly suppressed tumor growth. These results suggest that intratumoral injections of rR9-GRIM19 have potential as a novel anticancer therapy in STAT3c cancer due to their ability to inhibit STAT3-mediated signal transduction without major systemic side effects. Mol Cancer Ther; 9(8); 2333–43. ©2010 AACR.