文章：

整合素连接激酶：在其ILK中独特的癌症治疗靶点

Integrin-linked kinase: a cancer therapeutic target unique among its ILK

原文发布日期：2005-02-01

DOI: 10.1038/nrc1524

类型: Review Article

开放获取: 否

要点：

1. Integrin-linked kinase (ILK) is a β1-integrin cytoplasmic domain interacting protein, and functions as a scaffold in forming multiprotein complexes connecting integrins to the actin cytoskeleton and signalling pathways.
2. ILK is essential for embryonic development.
3. ILK activity is stimulated by adhesion to the extracellular matrix and by growth factors in a phosphatidylinositol 3-kinase (PI3K)-dependent manner.
4. Overexpression of ILK in epithelial cells induces epithelial–mesenchymal transition (EMT) by inhibiting E-cadherin expression, activates nuclear β-catenin and induces a transformed, tumorigenic phenotype.
5. Mammary epithelial cell specific expression of ILK in transgenic mice induces hyperplasia and tumour formation.
6. Overexpression or constitutive activation of ILK promotes cell survival by stimulating the phosphorylation of AKT on Ser473, and inhibiting ILK in cancer cells inhibits AKT phosphorylation and cell survival.
7. ILK activity is constitutively activated in PTEN-negative tumours, and inhibiting ILK induces apoptosis and cell-cycle arrest
8. ILK regulates tumour angiogenesis. ILK activation promotes vascular endothelial growth factor (VEGF) expression in tumour cells, and ILK has an essential role in VEGF-mediated endothelial activation and angiogenesis.
9. ILK expression and activity are increased in many types of cancer, such as prostate, colon, gastric and ovarian cancers, and malignant melanomas.
10. Small-molecule inhibitors of ILK have been identified and shown to inhibit cancer-cell growth, survival and invasion in vitro, and tumour growth and angiogenesis in vivo.

要点翻译：

1. 整合素连接激酶（ILK）是一种与β1-整合素胞质结构域相互作用的蛋白，其作为支架蛋白参与形成多蛋白复合物，将整合素与肌动蛋白细胞骨架及信号通路相连接。
2. ILK对胚胎发育至关重要。
3. 其活性受到细胞外基质粘附以及生长因子以磷脂酰肌醇3-激酶（PI3K）依赖方式的激活。
4. 在上皮细胞中过度表达ILK可通过抑制E-钙黏蛋白表达诱导上皮-间质转化（EMT），激活核β-连环蛋白并诱发转化性、致瘤性表型。
5. 转基因小鼠乳腺上皮细胞特异性表达ILK可诱导增生和肿瘤形成。
6. ILK的过表达或组成性激活通过刺激AKT蛋白Ser473位点磷酸化促进细胞存活，而在癌细胞中抑制ILK可阻断AKT磷酸化并抑制细胞存活。
7. PTEN阴性肿瘤中ILK活性呈组成性激活，抑制ILK可诱导细胞凋亡和细胞周期停滞。
8. ILK调控肿瘤血管生成：其激活促进肿瘤细胞中血管内皮生长因子（VEGF）表达，并在VEGF介导的内皮细胞激活和血管生成中起关键作用。
9. ILK的表达与活性在前列腺癌、结肠癌、胃癌、卵巢癌及恶性黑色素瘤等多种癌症中显著升高。
10. 目前已鉴定出小分子ILK抑制剂，研究证实其能在体外抑制癌细胞生长、存活和侵袭，在体内抑制肿瘤生长和血管生成。

英文摘要：

Cancer development requires the acquisition of several capabilities that include increased replicative potential, anchorage and growth-factor independence, evasion of apoptosis, angiogenesis, invasion of surrounding tissues and metastasis. One protein that has emerged as promoting many of these phenotypes when dysregulated is integrin-linked kinase (ILK), a unique intracellular adaptor and kinase that links the cell-adhesion receptors, integrins and growth factors to the actin cytoskeleton and to a range of signalling pathways. The recent findings of increased levels of ILK in various cancers, and that inhibition of ILK expression and activity is antitumorigenic, makes ILK an attractive target for cancer therapeutics.

摘要翻译： 

癌症的发生需要获得多种能力，包括增强的复制潜能、不依赖锚定和生长因子、逃避凋亡、血管生成、侵袭周围组织以及转移。当调控异常时，有一种蛋白——整合素连接激酶（ILK）——能够促进上述多种表型。ILK是一种独特的细胞内适配器和激酶，它将细胞黏附受体（整合素）和生长因子与肌动蛋白骨架以及多条信号通路连接起来。近期研究发现，ILK在多种癌症中表达升高，且抑制ILK的表达和活性具有抗肿瘤作用，这使得ILK成为癌症治疗的一个有吸引力的靶点。

原文链接：

Integrin-linked kinase: a cancer therapeutic target unique among its ILK