Inhibition of MMP-9 transcription and suppression of tumor metastasis by pyrrole-imidazole polyamide
Inhibition of MMP-9 transcription and suppression of tumor metastasis by pyrrole-imidazole polyamide
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DOI：
10.1111/j.1349-7006.2009.01435.x
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发表时间：
2010-03-01
期刊：
影响因子：
5.7
通讯作者：
Sugiyama, Hiroshi
中科院分区：
文献类型：
--
作者：
Wang, Xiaofei;Nagase, Hiroki;Sugiyama, Hiroshi
基质金属蛋白酶 (MMP)-9 是一种 92 kDa IV 型胶原酶，有助于肿瘤侵袭和转移，下调其表达的策略最终可能具有临床实用性。设计并合成了一种靶向 MMP-9 启动子的激活蛋白 1 (AP-1) 结合位点的吡咯-咪唑 (PI) 聚酰胺，作为肿瘤转移的基因沉默剂。合成产物表现出选择性DNA结合能力。 MMP-9 PI 聚酰胺显着抑制人乳腺癌细胞 (MDA-MB-231) 中 MMP-9 的 mRNA 表达、蛋白水平和酶活性。此外，通过体外伤口愈合和基质胶侵袭测定，MMP-9 PI 聚酰胺抑制迁移和侵袭。 FITC 标记的 PI 聚酰胺在与 MDA-MB-231 细胞孵育 45 分钟后定位在细胞核中，并在体外孵育后保留在细胞核中长达 96 小时。在不使用任何药物输送系统的情况下静脉注射后，它也能快速定位于小鼠许多组织的细胞核中，包括肝脏、肾脏和脾脏。此外，聚酰胺治疗显着减少了小鼠肝转移模型的转移。我们的结果表明，这种靶向 MMP-9 基因启动子的 PI 聚酰胺可以成为一种新型的抗转移 MMP-9 下调分子。 （癌症科学 2010 年；101：759-766）
Matrix metalloproteinase (MMP)-9, the 92-kDa type IV collagenase, contributes to tumor invasion and metastases, and strategies to down-regulate its expression could ultimately be of clinical utility. A pyrrole-imidazole (PI) polyamide that targets the activator protein-1 (AP-1)-binding site of the MMP-9 promoter was designed and synthesized as a gene-silencing agent for tumor metastases. The synthesized product showed selective DNA binding ability. The MMP-9 PI polyamide significantly inhibited MMP-9's mRNA expression, protein level, and enzymatic activity in human breast adenocarcinoma cells (MDA-MB-231). Furthermore, the MMP-9 PI polyamide inhibited migration and invasion by in vitro wound-healing and matrigel-invasion assay. The FITC-labeled PI polyamide was localized in nuclei in 45 min of incubation with an MDA-MB-231 cell and remained in the nuclei for up to 96 h after incubation in vitro. It was also quickly localized in the mouse cellular nuclei of many tissues, including liver, kidney, and spleen, after intravenous injection without using any drug-delivery system. Moreover, the polyamide treatment significantly decreased metastasis in a mouse model of liver metastasis. Our results suggest that this PI polyamide, which targets the MMP-9 gene promoter, can be a novel MMP-9 downregulating molecule for antimetastasis. (Cancer Sci 2010; 101: 759-766)