title: Cadmium induces Wnt signaling to upregulate proliferation and survival genes in sub-confluent kidney proximal tubule cells.
abstract: BACKGROUND
  The class 1 carcinogen cadmium (Cd2+) disrupts the E-cadherin/beta-catenin complex of epithelial adherens junctions (AJs) and causes renal cancer. Deregulation of E-cadherin adhesion and changes in Wnt/beta-catenin signaling are known to contribute to carcinogenesis.
  
  
  RESULTS
  We investigated Wnt signaling after Cd2+-induced E-cadherin disruption in sub-confluent cultured kidney proximal tubule cells (PTC). Cd2+ (25 microM, 3-9 h) caused nuclear translocation of beta-catenin and triggered a Wnt response measured by TOPflash reporter assays. Cd2+ reduced the interaction of beta-catenin with AJ components (E-cadherin, alpha-catenin) and increased binding to the transcription factor TCF4 of the Wnt pathway, which was upregulated and translocated to the nucleus. While Wnt target genes (c-Myc, cyclin D1 and ABCB1) were up-regulated by Cd2+, electromobility shift assays showed increased TCF4 binding to cyclin D1 and ABCB1 promoter sequences with Cd2+. Overexpression of wild-type and mutant TCF4 confirmed Cd2+-induced Wnt signaling. Wnt signaling elicited by Cd2+ was not observed in confluent non-proliferating cells, which showed increased E-cadherin expression. Overexpression of E-cadherin reduced Wnt signaling, PTC proliferation and Cd2+ toxicity. Cd2+ also induced reactive oxygen species dependent expression of the pro-apoptotic ER stress marker and Wnt suppressor CHOP/GADD153 which, however, did not abolish Wnt response and cell viability.
  
  
  CONCLUSIONS
  Cd2+ induces Wnt signaling in PTC. Hence, Cd2+ may facilitate carcinogenesis of PTC by promoting Wnt pathway-mediated proliferation and survival of pre-neoplastic cells.
authors.affiliation: ZBAF, Department of Physiology & Pathophysiology, University of Witten/Herdecke, Stockumer Strasse 12, D-58453 Witten, Germany. Prabir.Chakraborty@uni-wh.de
authors.forename: Prabir K
authors.initials: PK
authors.lastname: Chakraborty
authors.forename: Wing-Kee
authors.initials: WK
authors.lastname: Lee
authors.forename: Malte
authors.initials: M
authors.lastname: Molitor
authors.forename: Natascha A
authors.initials: NA
authors.lastname: Wolff
authors.forename: Frank
authors.initials: F
authors.lastname: Thévenod
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D002104:Cadmium / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation; D051153:Wnt Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015820:Cadherins; D002273:Carcinogens; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D002104:Cadmium
references.citation: J Biol Chem. 2004 Oct 8;279(41):43061-9
references.pmid: 15292248
references.citation: Adv Drug Deliv Rev. 2005 Apr 25;57(6):815-55
references.pmid: 15820555
references.citation: Oncogene. 1999 Nov 11;18(47):6615-20
references.pmid: 10597266
references.citation: Ann N Y Acad Sci. 2004 Apr;1014:155-63
references.pmid: 15153430
references.citation: Oncogene. 2008 Feb 7;27(7):966-75
references.pmid: 17700530
references.citation: FASEB J. 1999 Oct;13(13):1751-61
references.pmid: 10506578
references.citation: Cell. 2000 Jan 7;100(1):57-70
references.pmid: 10647931
references.citation: Cancer Res. 2001 Feb 15;61(4):1671-7
references.pmid: 11245482
references.citation: J Biol Chem. 2000 Jul 21;275(29):21883-8
references.pmid: 10896949
references.citation: Dev Dyn. 2005 Sep;234(1):132-42
references.pmid: 16010672
references.citation: Biometals. 2007 Oct;20(5):807-20
references.pmid: 17136310
references.citation: Cell. 1996 Oct 18;87(2):159-70
references.pmid: 8861899
references.citation: Mol Cell Biol. 2000 Jun;20(12):4238-52
references.pmid: 10825188
references.citation: Mol Cell Biol. 1996 Aug;16(8):4088-94
references.pmid: 8754807
references.citation: Kidney Int. 1996 Jul;50(1):125-34
references.pmid: 8807581
references.citation: Biochim Biophys Acta. 1999 Aug 12;1451(1):93-100
references.pmid: 10446391
references.citation: Cell. 2006 Nov 3;127(3):469-80
references.pmid: 17081971
references.citation: Toxicol Appl Pharmacol. 2009 Aug 1;238(3):315-26
references.pmid: 19233221
references.citation: J Biol Chem. 1999 Oct 29;274(44):31663-70
references.pmid: 10531375
references.citation: J Cell Biol. 1995 Apr;129(2):489-506
references.pmid: 7721948
references.citation: Clin Cancer Res. 2003 Jun;9(6):2121-32
references.pmid: 12796377
references.citation: J Cell Biol. 2009 Jul 27;186(2):219-28
references.pmid: 19620634
references.citation: J Cell Biol. 2004 Oct 25;167(2):339-49
references.pmid: 15492040
references.citation: Cells Tissues Organs. 2007;185(1-3):73-84
references.pmid: 17587811
references.citation: Cancer Res. 2008 May 15;68(10):3645-54
references.pmid: 18483246
references.citation: Nat Rev Mol Cell Biol. 2009 Jul;10(7):468-77
references.pmid: 19536106
references.citation: Anal Biochem. 1976 May 7;72:248-54
references.pmid: 942051
references.citation: Genes Cells. 1998 Jun;3(6):395-403
references.pmid: 9734785
references.citation: Int J Epidemiol. 2000 Dec;29(6):1014-24
references.pmid: 11101542
references.citation: J Am Soc Nephrol. 2009 Sep;20(9):1919-28
references.pmid: 19696224
references.citation: Occup Med (Lond). 2002 May;52(3):157-64
references.pmid: 12063361
references.citation: Lab Invest. 2005 Jun;85(6):768-79
references.pmid: 15806138
references.citation: J Biol Chem. 2008 Feb 15;283(7):4252-60
references.pmid: 18086661
references.citation: Nat Rev Cancer. 2008 May;8(5):387-98
references.pmid: 18432252
references.citation: Nucleic Acids Res. 1991 May 11;19(9):2499
references.pmid: 2041787
references.citation: Mutat Res. 2003 Dec 10;533(1-2):107-20
references.pmid: 14643415
references.citation: Biochem J. 2002 Dec 1;368(Pt 2):471-81
references.pmid: 12169098
references.citation: J Biol Chem. 2008 Aug 29;283(35):24061-76
references.pmid: 18559349
references.citation: Nature. 1999 Apr 1;398(6726):422-6
references.pmid: 10201372
references.citation: Carcinogenesis. 2002 Jan;23(1):107-14
references.pmid: 11756231
references.citation: Biochim Biophys Acta. 2009 Dec;1796(2):63-74
references.pmid: 19268509
references.citation: Cell Death Differ. 2007 Aug;14(8):1467-74
references.pmid: 17464326
references.citation: Toxicology. 2003 Nov 5;192(2-3):95-117
references.pmid: 14580780
references.citation: J Cell Sci. 1999 Dec;112 ( Pt 23):4415-23
references.pmid: 10564659
references.citation: Toxicol Appl Pharmacol. 2008 Jul 1;230(1):78-85
references.pmid: 18353411
references.citation: Mol Cancer. 2008 Jun 09;7:53
references.pmid: 18541010
references.citation: Cold Spring Harb Perspect Biol. 2009 Sep;1(3):a003053
references.pmid: 20066110
references.citation: Physiology (Bethesda). 2007 Oct;22:303-9
references.pmid: 17928543
references.citation: IARC Monogr Eval Carcinog Risks Hum. 1993;58:1-415
references.pmid: 8022054
references.citation: Am J Physiol. 1998 Jul;275(1):F143-53
references.pmid: 9689016
references.citation: Science. 2004 Mar 5;303(5663):1483-7
references.pmid: 15001769
references.citation: Toxicol Appl Pharmacol. 2002 Aug 1;182(3):255-65
references.pmid: 12183105
references.citation: J Biol Chem. 2000 Jan 21;275(3):1887-96
references.pmid: 10636889
references.citation: J Cell Sci. 1999 Apr;112 ( Pt 8):1237-45
references.pmid: 10085258
references.citation: J Cell Biol. 2001 Sep 17;154(6):1185-96
references.pmid: 11564756
references.citation: Arch Toxicol. 2008 Aug;82(8):493-512
references.pmid: 18496671
references.citation: Mol Cell Biol. 2001 Sep;21(17):5857-68
references.pmid: 11486025
references.citation: J Cell Sci. 2008 Jul 1;121(Pt 13):2224-34
references.pmid: 18565826
references.citation: Cancer Res. 2000 Sep 1;60(17):4761-6
references.pmid: 10987283
references.citation: Science. 1997 Mar 21;275(5307):1784-7
references.pmid: 9065401
references.citation: Oncogene. 2006 Jun 8;25(24):3397-407
references.pmid: 16434966