CXCL12 Chemokine Expression and Secretion Regulates Colorectal Carcinoma Cell Anoikis through Bim-Mediated Intrinsic Apoptosis 英文参考文献.docVIP

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CXCL12 Chemokine Expression and Secretion Regulates Colorectal Carcinoma Cell Anoikis through Bim-Mediated Intrinsic Apoptosis 英文参考文献.doc

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CXCL12 Chemokine Expression and Secretion Regulates Colorectal Carcinoma Cell Anoikis through Bim-Mediated Intrinsic Apoptosis 英文参考文献

CXCL12ChemokineExpressionandSecretionRegulates ColorectalCarcinomaCellAnoikisthroughBim-Mediated IntrinsicApoptosis LukeJ.Drury,MichaelK.Wendt¤,MichaelB.Dwinell* DepartmentofMicrobiologyandMolecularGenetics,MedicalCollegeofWisconsin,Milwaukee,Wisconsin,UnitedStatesofAmerica Abstract Background:Resistancetoanoikis,apoptosistriggeredbyalossofcellularadhesiontotheunderlyingextracellularmatrix, isahallmarkofmetastaticcancer.Previouslywehaveshownre-establishmentofCXCL12expressionincolorectalcarcinoma cells inhibits metastasis by enhancing anoikis sensitivity. The objective of these studies was to define the signaling mechanismsregulatingCXCL12-mediatedanoikis. Methodology/Principal Findings: Adhesion, examined by crystal violet staining, immunofluorescence microscopy, and immunoblot analysis indicated decreased focal adhesion signaling corresponding with loss of adhesion in cells constitutively simulated by CXCL12. Loss of adhesion was inhibited by pertussis toxin treatment, indicating CXCL12 regulating anoikis through Gai-protein coupled receptors. Non-adherent HCT116 and HT29 colorectal carcinoma cells expressing CXCL12 exhibited enhanced anoikis sensitivity by propidium iodide staining, caspase activity assays, and immunoblotcomparedtoGFPcontrolcells.CXCL12producingcarcinomasculturedonpoly-HEMAdisplayedheightened BimandlossofMcl-1andBcl-2precedingcytochromecrelease,andcaspase-9activation.RNAiknockdownofBimreversed anoikis sensitivity of CXCL12-expressing cells and fostered increased soft-agar foci formation and hepatic tumors in an orthotopicmousemodelofmetastasis. Conclusions/Significance:ThesedataindicateCXCL12providesabarriertometastasisbyincreasinganoikisviaactivation ofaBim-mediatedintrinsicapoptoticpathway.TheseresultsunderscoretheimportanceofretainingCXCL12expressionto sensitizecolorectalcarcinomastoanoikisandminimizetumorprogression. Citation: Drury LJ, Wendt MK, Dwinell MB (2010) CXCL12 Chemokine Expression and Secretion Regulates Colorectal Carcinoma Cell