Inhibition of integrin-linked kinase (ILK) suppresses activation of protein kinase B/Akt and induces cell cycle arrest and apoptosis of PTEN-mutant prostate cancer cells
Inhibition of integrin-linked kinase (ILK) suppresses activation of protein kinase B/Akt and induces cell cycle arrest and apoptosis of PTEN-mutant prostate cancer cells
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DOI：
10.1073/pnas.060579697
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发表时间：
2000-03-28
影响因子：
11.1
通讯作者：
Dedhar, S
中科院分区：
文献类型：
--
作者：
Persad, S;Attwell, S;Dedhar, S
PTEN是位于染色体10 q23上的肿瘤抑制基因，其编码蛋白质和磷脂磷酸酶。在许多人类恶性肿瘤中发现了PTEN的体细胞突变。并且表达的丧失或突变失活导致蛋白激酶B（PKB）/Akt通过Thr-308和Ser-473的增强的磷酸化而组成性活化。我们最近已经证明，整合素连接激酶（ILK）可以磷酸化PKB/Akt的丝氨酸-473在磷酸肌醇磷脂依赖性的方式。我们现在证明，ILK的活性在PTEN突变细胞中以不依赖于血清和锚定的方式组成性升高。并且将野生型（WT）PTEN转染到这些细胞中抑制ILK活性。在PTEN突变的前列腺癌细胞系PC-3和LNCaP中，ILK的激酶缺陷显性阴性形式的转染或暴露于小分子ILK抑制剂抑制了PKB/Akt在Ser-473上的组成性磷酸化，但不抑制Thr-308上的组成性磷酸化。将显性阴性ILK和WT PTEN转染到这些细胞中也导致PKB/Akt激酶活性的抑制。此外。显性阴性ILK或WT PTEN诱导G（1）期周期停滞和增强的细胞凋亡。一起这些数据表明ILK在PTEN依赖性细胞周期调节和存活中的关键作用，并表明ILK的抑制在PTEN突变肿瘤治疗中可能具有重要价值。
PTEN is a tumor suppressor gene located on chromosome 10q23 that encodes a protein and phospholipid phosphatase. Somatic mutations of PTEN are found in a number of human malignancies. and loss of expression, or mutational inactivation of PTEN, leads to the constitutive activation of protein kinase B (PKB)/Akt via enhanced phosphorylation of Thr-308 and Ser-473. We recently have demonstrated that the integrin-linked kinase (ILK) can phosphorylate PKB/Akt on Ser-473 in a phosphoinositide phospholipid-dependent manner. We now demonstrate that the activity of ILK is constitutively elevated in a serum- and anchorage-independent manner in PTEN-mutant cells. and transfection of wild-type (WT) PTEN into these cells inhibits ILK activity. Transfection of a kinase-deficient dominant-negative form of ILK or exposure to a small molecule ILK inhibitor suppresses the constitutive phosphorylation of PKB/Akt on Ser-473, but not on Thr-308, in the PTEN-mutant prostate carcinoma cell lines PC-3 and LNCaP. Transfection of dominant-negative ILK and WT PTEN into these cells also results in the inhibition of PKB/Akt kinase activity. Furthermore. dominant-negative ILK or WT PTEN induces G(1) phase cycle arrest and enhanced apoptosis. Together. these data demonstrate a critical role for ILK in PTEN-dependent cell cycle regulation and survival and indicate that inhibition of ILK may be of significant value in PTEN-mutant tumor therapy.