title: The insulin-like growth factor receptor I promotes motility and invasion of bladder cancer cells through Akt- and mitogen-activated protein kinase-dependent activation of paxillin.
abstract: The insulin-like growth factor receptor I (IGF-IR) plays an essential role in transformation by promoting cell growth and protecting cancer cells from apoptosis. Aberrant IGF-IR signaling is implicated in several types of tumors, including carcinomas of the lung, breast, prostate, pancreas, liver, and colon. However, the contribution of the IGF-IR to the development of the transformed phenotype in urothelial cells has not been clearly established. In this study we demonstrated that the IGF-IR is overexpressed in invasive bladder cancer tissues compared with nonmalignant controls. We have investigated the role of the IGF-IR in bladder cancer by using urothelial carcinoma-derived 5637 and T24 cells. Although activation of the IGF-IR did not appreciably affect their growth, it did promote migration and stimulate in vitro wound closure and invasion. These effects required the activation of the Akt and Mitogen-activated protein kinase (MAPK) pathways as well as IGF-I-induced Akt- and MAPK-dependent phosphorylation of paxillin, which relocated at dynamic focal adhesions and was necessary for promoting motility in bladder cancer cells. Our results provide the first evidence for a role of the IGF-IR in motility and invasion of bladder cancer cells and support the hypothesis that the IGF-IR may play a critical role in the establishment of the invasive phenotype in urothelial neoplasia. Thus, the IGF-IR may also serve as a novel biomarker for bladder cancer.
authors.affiliation: Department of Urology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: David
authors.initials: D
authors.lastname: Metalli
authors.forename: Francesca
authors.initials: F
authors.lastname: Lovat
authors.forename: Farida
authors.initials: F
authors.lastname: Tripodi
authors.forename: Marco
authors.initials: M
authors.lastname: Genua
authors.forename: Shi-Qiong
authors.initials: SQ
authors.lastname: Xu
authors.forename: Michela
authors.initials: M
authors.lastname: Spinelli
authors.forename: Lilia
authors.initials: L
authors.lastname: Alberghina
authors.forename: Marco
authors.initials: M
authors.lastname: Vanoni
authors.forename: Raffaele
authors.initials: R
authors.lastname: Baffa
authors.forename: Leonard G
authors.initials: LG
authors.lastname: Gomella
authors.forename: Renato V
authors.initials: RV
authors.lastname: Iozzo
authors.forename: Andrea
authors.initials: A
authors.lastname: Morrione
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D002471:Cell Transformation, Neoplastic; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D051419:Paxillin / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000473:pathology*
chemical_list: D051419:Paxillin; D034741:RNA, Small Interfering; D017526:Receptor, IGF Type 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases
references.citation: J Cell Biol. 2004 Nov 22;167(4):745-56
references.pmid: 15557124
references.citation: Cell. 1993 Oct 8;75(1):73-82
references.pmid: 8402902
references.citation: Exp Cell Res. 1997 Feb 25;231(1):149-62
references.pmid: 9056422
references.citation: Nature. 1979 Oct 4;281(5730):390-2
references.pmid: 481605
references.citation: Mol Cell. 2004 Oct 22;16(2):257-67
references.pmid: 15494312
references.citation: Oncogene. 2003 Sep 29;22(42):6589-97
references.pmid: 14528284
references.citation: Carcinogenesis. 2009 May;30(5):861-8
references.pmid: 19237611
references.citation: Mol Biol Cell. 2008 May;19(5):2003-13
references.pmid: 18305103
references.citation: BJU Int. 2007 Dec;100(6):1396-401
references.pmid: 17645417
references.citation: Cancer Metastasis Rev. 2009 Jun;28(1-2):35-49
references.pmid: 19169797
references.citation: Clin Cancer Res. 2007 Sep 15;13(18 Pt 2):5549s-5555s
references.pmid: 17875788
references.citation: J Cell Biochem. 1999;Suppl 32-33:68-75
references.pmid: 10629105
references.citation: Oncogene. 2000 Nov 20;19(49):5574-81
references.pmid: 11114737
references.citation: Mol Cell. 2003 Nov;12(5):1275-85
references.pmid: 14636584
references.citation: Exp Cell Res. 1999 Nov 1;252(2):439-48
references.pmid: 10527634
references.citation: J Biol Chem. 1996 Feb 2;271(5):2443-7
references.pmid: 8576205
references.citation: Cancer Res. 2000 Apr 15;60(8):2263-72
references.pmid: 10786694
references.citation: Genes Dev. 1997 Dec 1;11(23):3128-42
references.pmid: 9389646
references.citation: CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49
references.pmid: 19474385
references.citation: Cancer Res. 1995 Jan 15;55(2):249-52
references.pmid: 7812953
references.citation: Biochim Biophys Acta. 1997 Jun 7;1332(3):F105-26
references.pmid: 9196021
references.citation: Annu Rev Pathol. 2009;4:251-85
references.pmid: 18840072
references.citation: J Biol Chem. 2001 Jul 13;276(28):25990-6
references.pmid: 11352919
references.citation: Cancer Res. 2006 Jul 15;66(14):7103-10
references.pmid: 16849556
references.citation: Mol Cell Biol. 2007 Apr;27(8):3165-75
references.pmid: 17296734
references.citation: J Clin Invest. 2009 Feb;119(2):252-66
references.pmid: 19147981
references.citation: Mol Cell Biol. 2006 Apr;26(7):2857-68
references.pmid: 16537926
references.citation: Clin Cancer Res. 2008 Oct 15;14(20):6364-70
references.pmid: 18927274
references.citation: Nat Cell Biol. 2004 Feb;6(2):154-61
references.pmid: 14743221
references.citation: Int J Clin Oncol. 2008 Aug;13(4):287-97
references.pmid: 18704628
references.citation: Nat Rev Mol Cell Biol. 2004 Oct;5(10):816-26
references.pmid: 15459662
references.citation: Nat Rev Cancer. 2004 Jul;4(7):505-18
references.pmid: 15229476
references.citation: J Cell Biol. 2000 Mar 6;148(5):957-70
references.pmid: 10704446
references.citation: Isr Med Assoc J. 1999 Sep;1(1):25-30
references.pmid: 11370118
references.citation: Mol Cell Biol. 1999 Oct;19(10):7203-15
references.pmid: 10490655
references.citation: Growth Horm IGF Res. 2000 Apr;10 Suppl A:S12-3
references.pmid: 10984274
references.citation: Mol Cell Endocrinol. 1988 Oct;59(3):205-12
references.pmid: 2903103
references.citation: Am J Pathol. 2009 Mar;174(3):1037-47
references.pmid: 19179604
references.citation: Cancer Res. 2001 Sep 15;61(18):6747-54
references.pmid: 11559546
references.citation: Glycobiology. 2004 Feb;14(2):147-55
references.pmid: 14576171
references.citation: J Cell Physiol. 2008 Aug;216(2):426-37
references.pmid: 18286479