Inhibition of integrin-linked kinase by QLT0254 inhibits Akt-dependent pathways and is growth inhibitory in orthotopic primary pancreatic cancer xenografts
Inhibition of integrin-linked kinase by QLT0254 inhibits Akt-dependent pathways and is growth inhibitory in orthotopic primary pancreatic cancer xenografts
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DOI：
10.1158/0008-5472.can-04-2940
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发表时间：
2005-02-15
期刊：
影响因子：
11.2
通讯作者：
Hedley, DW
中科院分区：
文献类型：
--
作者：
Yau, CYF;Wheeler, JJ;Hedley, DW
整合素连接激酶（ILK）将整合素和生长因子偶联至下游信号传导途径，所述下游信号传导途径涉及磷脂酰肌醇3-激酶、蛋白激酶B/Akt（PKB/Akt）和糖原合成酶激酶-30。在胰腺癌的原位原发性异种移植模型中测试ILK抑制剂QLTO 254的抗癌作用。通过免疫组织化学和蛋白质印迹法测量了QLT 0254单次给药对PKB/Akt磷酸化的药效学作用，结果显示2小时后降低>80%，随后在24小时内恢复，与该化合物在小鼠中的药代动力学特征一致。QLT 0254还抑制了磷酸化PKB Thr 308、横纹肌肉瘤中的叉头、S6 K1、S6、4 E-BP 1以及信号转导和转录激活因子3 Tyr（705）和Ser（727）蛋白水平，并抑制了ILK。然而，我们没有观察到QLT 0254处理对磷酸肌醇依赖性激酶1、糖原合成酶激酶-30和细胞外信号调节激酶磷酸化或对总PKB和ILK蛋白表达水平的影响。在肿瘤生长抑制实验中，与溶媒对照相比，每日用QLT 0254治疗3周耐受性良好，并产生显著的肿瘤生长抑制（P = 0.001）。当施用单剂量的QLT 0254和化疗剂吉西他滨时，与媒介物对照相比，联合治疗组中的急性细胞凋亡显著增加5.4倍（P = 0.002）。然而，QLT 0254对增殖的急性效应没有统计学显著性。这些结果表明，体内证据表明，ILK在体内致癌磷脂酰肌醇3-激酶/PKB信号传导中起着重要作用，对雷帕霉素的哺乳动物靶标、信号转导和转录激活因子3以及横纹肌肉瘤信号传导途径中的叉头有重要影响，这表明ILK抑制剂可能在胰腺癌患者中显示出活性。
Integrin-linked kinase (ILK) couples integrins and growth factors to downstream signaling pathways involving phosphatidylinositol 3-kinase, protein kinase B/Akt (PKB/Akt), and glycogen synthase kinase-30. The anticancer effects of ILK inhibitor QLTO 254 were tested in an orthotopic primary xenograft model of pancreatic cancer. The pharmacodynamic effects of a single dose of QLT0254 on the phosphorylation of PKB/Akt were measured by immunohistochemistry and Western blotting, and showed a decrease of >80% after 2 hours, followed by recovery over 24 hours, consistent with the pharmacokinetic profile of this compound in mice. There was also suppression in phosphorylated PKB Thr 308, forkhead in rhabdomyosarcoma, S6K1, S6, 4E-BP1, and signal transducers and activators of transcription 3 Tyr(705) and Ser(727) protein levels with ILK inhibition by QLT0254. However, we did not observe an effect on phosphoinositide-dependent kinase 1, glycogen synthase kinase-30, and extracellular signal-regulated kinase phosphorylation or on total PKB and ILK protein expression levels with QLT0254 treatment. In tumor growth inhibition experiments, daily treatment with QLT0254 for 3 weeks was well tolerated and produced significant tumor growth inhibition compared with vehicle control (P = 0.001). When a single dose of QLT0254 and chemotherapy agent gemcitabine was administered, there was a significant 5.4-fold increase in acute apoptosis in the combination therapy group compared with vehicle controls (P = 0.002). However, the acute effects of QLT0254 on proliferation were not statistically significant. These results show in vivo evidence that ILK plays a prominent role in oncogenic phosphatidylinositol 3-kinase/PKB signaling in vivo with major impact on the mammalian target of rapamycin, signal transducers and activators of transcription 3, and forkhead in rhadomyosarcoma signaling pathways, suggesting that ILK inhibitors might show activity in pancreatic cancer patients.