title: Phosphoglycerate kinase 1 a promoting enzyme for peritoneal dissemination in gastric cancer.
abstract: Peritoneal carcinomatosis is a frequent finding in gastric cancer associated with a poor prognosis. The features that enable gastric tumors to disseminate are poorly understood until now. Previously, we showed elevated mRNA levels of phosphoglycerate kinase 1 (PGK1), an adenosine triphosphate-generating enzyme in the glycolytic pathway, the chemokine receptor 4 (CXCR4), the corresponding chemokine ligand 12 (CXCL12) and beta-catenin in specimens from gastric cancer patients with peritoneal carcinomatosis. In this study, the influence of PGK1 on CXCR4 and beta-catenin was assessed as well as the invasiveness of PGK1 overexpressing cancer cells. In this current study, we found that PGK1 regulates the expression of CXCR4 and beta-catenin at the mRNA and protein levels. On the other hand, CXCR4 regulates the expression of PGK1. Plasmid-mediated overexpression of PGK1 dramatically increased the invasiveness of gastric cancer cells. Interestingly, inhibition of CXCR4 in cells overexpressing PGK1 produced only a moderate reduction of invasiveness suggesting that, PGK1 itself has a critical role in tumor invasiveness. Immunohistochemistry in specimens from diffuse gastric cancer patients also revealed an overexpression of PGK1 in patients with development of peritoneal carcinomatosis. Therefore, PGK1 may be a crucial enzyme in peritoneal dissemination. Together these findings suggest that the enhanced expression of PGK1 and its signaling targets CXCR4 and beta-catenin in gastric cancer cells promote peritoneal carcinomatosis. Thus, PGK1 may serve as prognostic marker and/or be a potential therapeutic target to prevent dissemination of gastric carcinoma cells into the peritoneum.
authors.affiliation: Department of General Visceral, Transplant Surgery Comprehensive Cancer Center, University of Tuebingen, D-72076 Tuebingen, Germany. derek.zieker@med.uni-tuebingen.de
authors.forename: Derek
authors.initials: D
authors.lastname: Zieker
authors.forename: Ingmar
authors.initials: I
authors.lastname: Königsrainer
authors.forename: Isabel
authors.initials: I
authors.lastname: Tritschler
authors.forename: Markus
authors.initials: M
authors.lastname: Löffler
authors.forename: Stefan
authors.initials: S
authors.lastname: Beckert
authors.forename: Frank
authors.initials: F
authors.lastname: Traub
authors.forename: Kay
authors.initials: K
authors.lastname: Nieselt
authors.forename: Sarah
authors.initials: S
authors.lastname: Bühler
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.forename: Jochen
authors.initials: J
authors.lastname: Gaedcke
authors.forename: Russell S
authors.initials: RS
authors.lastname: Taichman
authors.forename: Hinnak
authors.initials: H
authors.lastname: Northoff
authors.forename: Björn L D M
authors.initials: BL
authors.lastname: Brücher
authors.forename: Alfred
authors.initials: A
authors.lastname: Königsrainer
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008954:Models, Biological; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D010735:Phosphoglycerate Kinase / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; C527276:CXCR4 protein, human; D019718:Receptors, CXCR4; D051176:beta Catenin; D010735:Phosphoglycerate Kinase
references.citation: Am J Respir Cell Mol Biol. 2004 May;30(5):671-7
references.pmid: 14672915
references.citation: Biochim Biophys Acta. 2004 Apr 1;1691(1):17-22
references.pmid: 15053920
references.citation: CA Cancer J Clin. 1999 Jan-Feb;49(1):33-64, 1
references.pmid: 10200776
references.citation: Biochem Biophys Res Commun. 1998 Nov 18;252(2):368-72
references.pmid: 9826536
references.citation: Blood. 2002 Sep 1;100(5):1551-8
references.pmid: 12176869
references.citation: J Biol Chem. 2002 Mar 29;277(13):11336-44
references.pmid: 11792709
references.citation: Cancer Res. 2002 Mar 15;62(6):1832-7
references.pmid: 11912162
references.citation: Am J Surg. 1999 Sep;178(3):256-62
references.pmid: 10527450
references.citation: Cancer Res. 2006 May 1;66(9):4734-41
references.pmid: 16651426
references.citation: J Leukoc Biol. 2001 Feb;69(2):263-70
references.pmid: 11272277
references.citation: Science. 1956 Aug 10;124(3215):269-70
references.pmid: 13351639
references.citation: Nat Immunol. 2001 Feb;2(2):108-15
references.pmid: 11175802
references.citation: Cancer Res. 2000 Sep 1;60(17):4761-6
references.pmid: 10987283
references.citation: Cancer Res. 2007 Jan 1;67(1):149-59
references.pmid: 17210694
references.citation: Proteomics. 2006 Apr;6(7):2259-72
references.pmid: 16493704
references.citation: Mol Cell Proteomics. 2005 Nov;4(11):1686-96
references.pmid: 16048908
references.citation: World J Gastroenterol. 2008 Aug 14;14(30):4721-4
references.pmid: 18720530
references.citation: Gastroenterology. 2005 Oct;129(4):1237-50
references.pmid: 16230077
references.citation: Cell Physiol Biochem. 2008;21(5-6):429-36
references.pmid: 18453750
references.citation: Oncogene. 2008 Feb 28;27(10):1461-71
references.pmid: 17724466
references.citation: Cancer Res. 2006 Feb 15;66(4):2181-7
references.pmid: 16489019
references.citation: Biotechnol Bioeng. 2008 Aug 15;100(6):1205-13
references.pmid: 18553401
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Anticancer Res. 2002 Jul-Aug;22(4):1933-41
references.pmid: 12174867