title: PTTG induces EMT through integrin αVβ3-focal adhesion kinase signaling in lung cancer cells.
abstract: Pituitary tumor transforming gene (PTTG) is a well-studied oncogene for its role in tumorigenesis and serves as a marker of malignancy in several cancer types including lung. In the present study, we defined the role of PTTG in actin cytoskeleton remodeling, cell migration and induction of epithelial mesenchymal transition (EMT) through the regulation of integrin α(V)β(3)-FAK (focal adhesion kinase) signaling pathway. Overexpression of PTTG through an adenovirus vector resulted in a significant increase in the expression of integrins α(V) and β(3), a process that was reversed with the downregulation of PTTG expression through the use of an adenovirus expressing PTTG-specific small interfering RNA (siRNA). Western blot analysis of cells infected with adenovirus PTTG cDNA resulted in increased FAK and enhanced expression of adhesion complex molecules paxillin, metavincullin, and talin. Furthermore, downstream signaling genes Rac1, RhoA, Cdc42 and DOCK180 showed upregulation upon PTTG overexpression. This process was dependent on integrin α(V), as blockage by antagonist echistatin (RGD peptide) or α(V)-specific siRNA resulted in a decrease in FAK and subsequent adhesion molecules. Actin cytoskeleton disruption was detected as a result of integrin-FAK signaling by PTTG as well as enhanced cell motility. Taken together, our results suggest for the first time an important role of PTTG in regulation of integrins α(V) and β(3) and adhesion-complex proteins leading to induction of EMT.
authors.affiliation: James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA.
authors.forename: P P
authors.initials: PP
authors.lastname: Shah
authors.forename: M Y
authors.initials: MY
authors.lastname: Fong
authors.forename: S S
authors.initials: SS
authors.lastname: Kakar
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics; D015820:Cadherins / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D009363:Neoplasm Proteins / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D064249:Securin; D015398:Signal Transduction / Q000187:drug effects; D014746:Vimentin / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D015820:Cadherins; D039302:Integrin alphaVbeta3; D009363:Neoplasm Proteins; D009842:Oligopeptides; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D064249:Securin; D014746:Vimentin; C578002:pituitary tumor-transforming protein 1, human; C047981:arginyl-glycyl-aspartic acid; D051416:Focal Adhesion Protein-Tyrosine Kinases
references.citation: Nat Cell Biol. 2000 Dec;2(12):E231-6
references.pmid: 11146675
references.citation: Mol Cell Biol. 2002 Apr;22(8):2751-60
references.pmid: 11909967
references.citation: J Biol Chem. 1999 Jan 29;274(5):3001-8
references.pmid: 9915838
references.citation: J Biol Chem. 2008 May 9;283(19):13243-51
references.pmid: 18326486
references.citation: Cancer Res. 2009 Apr 15;69(8):3283-90
references.pmid: 19351864
references.citation: Cells Tissues Organs. 2007;185(1-3):146-56
references.pmid: 17587820
references.citation: Int J Oncol. 2007 Jul;31(1):137-43
references.pmid: 17549414
references.citation: Curr Opin Cell Biol. 2005 Oct;17(5):548-58
references.pmid: 16098727
references.citation: Cancer Metastasis Rev. 2005 Sep;24(3):425-39
references.pmid: 16258730
references.citation: Annu Rev Cell Dev Biol. 1996;12:697-715
references.pmid: 8970741
references.citation: Neoplasia. 2005 Mar;7(3):271-9
references.pmid: 15799827
references.citation: Cancer Metastasis Rev. 2009 Jun;28(1-2):15-33
references.pmid: 19169796
references.citation: J Clin Endocrinol Metab. 2005 Jun;90(6):3715-23
references.pmid: 15769981
references.citation: Nan Fang Yi Ke Da Xue Xue Bao. 2010 Jul;30(7):1712-4
references.pmid: 20650808
references.citation: J Biol Chem. 2004 Oct 22;279(43):44490-6
references.pmid: 15308668
references.citation: Proc Soc Exp Biol Med. 1999 Nov;222(2):124-38
references.pmid: 10564536
references.citation: Science. 1999 Jul 16;285(5426):418-22
references.pmid: 10411507
references.citation: Annu Rev Cell Dev Biol. 2003;19:173-206
references.pmid: 14570568
references.citation: Exp Cell Res. 2008 Feb 1;314(3):478-88
references.pmid: 18067889
references.citation: Oncogene. 2010 Oct 21;29(42):5741-54
references.pmid: 20697346
references.citation: Mol Endocrinol. 1999 Jan;13(1):156-66
references.pmid: 9892021
references.citation: J Clin Invest. 1991 Dec;88(6):1924-32
references.pmid: 1721625
references.citation: Dev Cell. 2002 Sep;3(3):367-81
references.pmid: 12361600
references.citation: J Biol Chem. 1991 Oct 15;266(29):19543-50
references.pmid: 1717468
references.citation: Hepatology. 2006 May;43(5):1042-52
references.pmid: 16628636
references.citation: Nat Cell Biol. 2005 May;7(5):510-6
references.pmid: 15852002
references.citation: J Cell Biol. 2002 Dec 23;159(6):1071-86
references.pmid: 12486108
references.citation: Cancer Res. 2007 Aug 1;67(15):7203-11
references.pmid: 17671188
references.citation: Cell Growth Differ. 1997 Jan;8(1):83-90
references.pmid: 8993837
references.citation: Gastroenterol Clin Biol. 2010 Oct;34(10):523-8
references.pmid: 20615641
references.citation: Mol Endocrinol. 1997 Apr;11(4):433-41
references.pmid: 9092795
references.citation: Mol Cell Biol. 1998 May;18(5):3044-58
references.pmid: 9566923
references.citation: Baillieres Best Pract Res Clin Endocrinol Metab. 1999 Oct;13(3):367-80
references.pmid: 10909429
references.citation: J Cell Biol. 1997 Jun 16;137(6):1403-19
references.pmid: 9182671
references.citation: Cell Biol Int. 2002;26(5):463-76
references.pmid: 12095232
references.citation: Curr Biol. 1998 May 21;8(11):633-41
references.pmid: 9635190
references.citation: Exp Cell Res. 1997 Feb 25;231(1):14-26
references.pmid: 9056408
references.citation: Development. 2007 Apr;134(8):1481-90
references.pmid: 17344227
references.citation: Dev Dyn. 1994 Dec;201(4):378-93
references.pmid: 7534501
references.citation: Cancer Res. 2010 Oct 1;70(19):7591-9
references.pmid: 20841470
references.citation: J Invest Dermatol. 2000 Oct;115(4):625-32
references.pmid: 10998134
references.citation: Curr Opin Cell Biol. 2003 Dec;15(6):740-6
references.pmid: 14644200
references.citation: Biochem Mol Biol Int. 1999 May;47(5):891-7
references.pmid: 10365261
references.citation: Mol Cancer. 2006 Nov 10;5:61
references.pmid: 17096843
references.citation: Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1557-61
references.pmid: 1371877
references.citation: Cardiovasc Res. 2004 Aug 15;63(3):381-90
references.pmid: 15276463
references.citation: Cell Motil Cytoskeleton. 2002 Feb;51(2):76-88
references.pmid: 11921165
references.citation: Structure. 2002 Mar;10(3):319-27
references.pmid: 12005431
references.citation: J Cell Biol. 1995 Sep;130(5):1181-7
references.pmid: 7657702
references.citation: J Mammary Gland Biol Neoplasia. 2007 Sep;12(2-3):127-33
references.pmid: 17564818
references.citation: Cell. 2002 Sep 20;110(6):673-87
references.pmid: 12297042
references.citation: Oncogene. 2010 Dec 9;29(49):6485-98
references.pmid: 20802523
references.citation: Int J Oncol. 2006 Aug;29(2):387-95
references.pmid: 16820881
references.citation: Anticancer Res. 2003 Sep-Oct;23(5A):3775-82
references.pmid: 14666677
references.citation: Lab Invest. 2004 Aug;84(8):999-1012
references.pmid: 15195114
references.citation: Nat Struct Biol. 2002 Feb;9(2):101-6
references.pmid: 11799401
references.citation: J Cell Biol. 2000 Mar 6;148(5):957-70
references.pmid: 10704446
references.citation: Mol Cell Biol. 2001 Aug;21(16):5332-45
references.pmid: 11463817
references.citation: Cancer Res. 1999 Apr 1;59(7):1655-64
references.pmid: 10197643
references.citation: Jpn J Clin Oncol. 2002 Jul;32(7):233-7
references.pmid: 12324572
references.citation: Tumour Biol. 2010 Jan;31(1):59-67
references.pmid: 20237902
references.citation: Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9482-7
references.pmid: 12874388
references.citation: Mol Cancer. 2005 Jan 13;4(1):3
references.pmid: 15649325
references.citation: Cell. 2004 Jun 25;117(7):927-39
references.pmid: 15210113
references.citation: BMC Genomics. 2009 Dec 03;10:577
references.pmid: 19958546
references.citation: Mol Cell Biol. 2004 Sep;24(18):8113-33
references.pmid: 15340073
references.citation: J Cell Sci. 2003 Apr 15;116(Pt 8):1409-16
references.pmid: 12640026
references.citation: Mol Cell Biochem. 2010 Jul;340(1-2):21-9
references.pmid: 20177740
references.citation: J Cell Physiol. 2007 Dec;213(3):565-73
references.pmid: 17680633
references.citation: Nat Rev Cancer. 2005 Jul;5(7):505-15
references.pmid: 16069815
references.citation: Cancer Metastasis Rev. 2009 Jun;28(1-2):151-66
references.pmid: 19153669
references.citation: Breast. 2004 Feb;13(1):80-1
references.pmid: 14759723
references.citation: J Mammary Gland Biol Neoplasia. 2010 Jun;15(2):117-34
references.pmid: 20490631
references.citation: J Cell Biol. 1998 Feb 23;140(4):961-72
references.pmid: 9472046
references.citation: Princess Takamatsu Symp. 1994;24:99-105
references.pmid: 8983067
references.citation: Oncogene. 2004 Oct 18;23(48):7928-46
references.pmid: 15489911
references.citation: Cancer Res. 2006 Sep 1;66(17):8319-26
references.pmid: 16951136
references.citation: Cytogenet Cell Genet. 1999;84(3-4):211-6
references.pmid: 10393434
references.citation: J Proteome Res. 2006 May;5(5):1143-54
references.pmid: 16674103
references.citation: Biochem Biophys Res Commun. 2005 May 27;331(1):86-92
references.pmid: 15845362
references.citation: Int J Biol Markers. 2010 Jan-Mar;25(1):38-45
references.pmid: 20306451
references.citation: Oncogene. 2005 Aug 29;24(37):5764-74
references.pmid: 16123809