Parathyroid hormone-related protein induces cell survival in human renal cell carcinoma through the PI3K-Akt pathway: evidence for a critical role for integrin-linked kinase and nuclear factor kappa B
Parathyroid hormone-related protein induces cell survival in human renal cell carcinoma through the PI3K-Akt pathway: evidence for a critical role for integrin-linked kinase and nuclear factor kappa B
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DOI：
10.1093/carcin/bgm106
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发表时间：
2007-09-01
期刊：
影响因子：
4.7
通讯作者：
Massfelder, Thierry
中科院分区：
文献类型：
--
作者：
Agouni, Abdelali;Sourbier, Carole;Massfelder, Thierry
我们最近发现，甲状旁腺素相关蛋白（PTHrP），一种类似腺嘌呤的多聚蛋白，通过抑制肿瘤细胞凋亡对人肾细胞癌（RCC）的生长至关重要。在这里，我们探讨了PTHrP控制肿瘤细胞存活的机制。使用磷酸肌醇3-激酶（PI 3 K）的特异性抑制剂和Akt激酶的RNA干扰耗竭，我们建立了PTHrP是参与人RCC中该通路的组成性激活的主要因素之一，独立于von Hippel-Lindau（VHL）肿瘤抑制基因表达。有趣的是，PTHrP诱导Akt在S473的磷酸化，但对T308的磷酸化没有影响。通过转染整合素连接激酶（ILK）的结构和RNA干扰，我们提供的证据表明，ILK参与人肾细胞癌细胞的生存。PTHrP激活ILK，然后ILK作为磷酸肌醇依赖性激酶（PDK）2或促进蛋白在S473磷酸化Akt。在测试的其他激酶中，仅ILK显示在RCC中发挥这种功能。通过特异性抑制剂、蛋白质印迹和转录检测，我们确定核因子κ B（NF-κ B B）是PTHrP调控的下游Akt靶点。由于RCC对目前的治疗仍然难治，我们的研究结果表明，PI 3 K/ILK/Akt/NF-κ B轴是一个有希望的治疗干预的目标。
We have recently shown that parathyroid hormone-related protein (PTHrP), a cytokine-like polyprotein, is critical for human renal cell carcinoma (RCC) growth by inhibiting tumor cell apoptosis. Here, we have explored mechanisms by which PTHrP controls tumor cell survival. Using specific inhibitors of phosphoinositide 3-kinase (PI3K) and depletion of Akt kinase by RNA interference, we established that PTHrP is one of the main factor involved in the constitutive activation of this pathway in human RCC, independently of von Hippel-Lindau (VHL) tumor suppressor gene expression. Interestingly, PTHrP induced phosphorylation of Akt at S473 but had no influence on phosphorylation at T308. Through transfection with integrin-linked kinase (ILK) constructs and RNA interference, we provide evidence that ILK is involved in human RCC cell survival. PTHrP activates ILK which then acts as a phosphoinositide-dependent kinase (PDK)2 or a facilitator protein to phosphorylate Akt at S473. Among other kinases tested, only ILK was shown to exert this function in RCC. Using specific inhibitors, western blot and transcription assay, we identified nuclear factor kappa B (NF-kappa B) as the downstream Akt target regulated by PTHrP. Since RCC remains refractory to current therapies, our results establish that the PI3K/ILK/Akt/NF-kappa B axis is a promising target for therapeutic intervention.