Inserm U1113, University of Strasbourg, Strasbourg, France.
Department of Pathology, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Int J Cancer. 2015 Oct 1;137(7):1549-59. doi: 10.1002/ijc.29522. Epub 2015 Apr 9.
Human conventional renal cell carcinoma (CCC) remains resistant to current therapies. Focal Adhesion Kinase (FAK) is upregulated in many epithelial tumors and clearly implicated in nearly all facets of cancer. However, only few reports have assessed whether FAK may be associated with renal tumorigenesis. In this study, we investigated the potential role of FAK in the growth of human CCC using a panel of CCC cell lines expressing or not the von Hippel-Lindau (VHL) tumor suppressor gene as well as normal/tumoral renal tissue pairs. FAK was found constitutively expressed in human CCC both in culture cells and freshly harvested tumors obtained from patients. We showed that CCC cell growth was dramatically reduced in FAK-depleted cells or after FAK inhibition with various inhibitors and this effect was obtained through inhibition of cell proliferation and induction of cell apoptosis. Additionally, our results indicated that FAK knockdown decreased CCC cell migration and invasion. More importantly, depletion or pharmacological inhibition of FAK substantially inhibited tumor growth in vivo. Interestingly, investigations of the molecular mechanism revealed loss of FAK phosphorylation during renal tumorigenesis impacting multiple signaling pathways. Taken together, our findings reveal a previously uncharacterized role of FAK in CCC whereby FAK exerts oncogenic properties through a non canonical signaling pathway involving its scaffolding kinase-independent properties. Therefore, targeting the FAK scaffold may represent a promising approach for developing innovative and highly specific therapies in human CCC.
人类传统的肾细胞癌（CCC）仍然对当前的治疗方法具有抗性。粘着斑激酶（FAK）在许多上皮肿瘤中上调，并明显参与癌症的几乎所有方面。然而，只有少数报道评估了 FAK 是否与肾肿瘤发生有关。在这项研究中，我们使用一组表达或不表达 von Hippel-Lindau（VHL）肿瘤抑制基因的 CCC 细胞系以及正常/肿瘤肾组织对，研究了 FAK 在人 CCC 生长中的潜在作用。我们发现 FAK 在人 CCC 中无论是在培养细胞中还是在从患者中获得的新鲜肿瘤中都持续表达。我们表明，在 FAK 耗竭的细胞中或在用各种抑制剂抑制 FAK 后，CCC 细胞的生长显著减少，这种作用是通过抑制细胞增殖和诱导细胞凋亡来实现的。此外，我们的结果表明，FAK 敲低减少了 CCC 细胞的迁移和侵袭。更重要的是，FAK 的耗竭或药理学抑制在体内显著抑制了肿瘤的生长。有趣的是，对分子机制的研究表明，在肾肿瘤发生过程中 FAK 的磷酸化丢失会影响多种信号通路。总之，我们的研究结果揭示了 FAK 在 CCC 中的一个以前未被描述的作用，即 FAK 通过涉及其支架激酶非依赖性特性的非典型信号通路发挥致癌特性。因此，靶向 FAK 支架可能代表了开发人 CCC 中创新和高度特异性治疗方法的有前途的方法。
