title: Targeting FAK scaffold functions inhibits human renal cell carcinoma growth.
abstract: 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.
authors: Inserm U1113, University of Strasbourg, Strasbourg, France.
authors: Claire
authors: C
authors: Béraud
authors: Inserm U1113, University of Strasbourg, Strasbourg, France.
authors: Valérian
authors: V
authors: Dormoy
authors: Inserm U1113, University of Strasbourg, Strasbourg, France.
authors: Sabrina
authors: S
authors: Danilin
authors: Department of Pathology, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
authors: Véronique
authors: V
authors: Lindner
authors: Inserm U1113, University of Strasbourg, Strasbourg, France.
authors: Audrey
authors: A
authors: Béthry
authors: Inserm U1113, University of Strasbourg, Strasbourg, France.
authors: Mazène
authors: M
authors: Hochane
authors: Inserm U1113, University of Strasbourg, Strasbourg, France.
authors: Catherine
authors: C
authors: Coquard
authors: Inserm U1113, University of Strasbourg, Strasbourg, France.
authors: Mariette
authors: M
authors: Barthelmebs
authors: Department of Urology, Nouvel Hôpital Civil De Strasbourg, Strasbourg, France.
authors: Didier
authors: D
authors: Jacqmin
authors: Department of Urology, Nouvel Hôpital Civil De Strasbourg, Strasbourg, France.
authors: Hervé
authors: H
authors: Lang
authors: Inserm U1113, University of Strasbourg, Strasbourg, France.
authors: Thierry
authors: T
authors: Massfelder
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors* / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000096:biosynthesis / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; C497446:VHL protein, human
keywords: FAK; human renal cell carcinoma; mouse xenograft models; tumorigenesis