title: Anterior gradient protein-2 is a regulator of cellular adhesion in prostate cancer.
abstract: Anterior Gradient Protein (AGR-2) is reported to be over-expressed in many epithelial cancers and promotes metastasis. A clear-cut mechanism for its observed function(s) has not been previously identified. We found significant upregulation of AGR-2 expression in a bone metastatic prostate cancer cell line, PC3, following culturing in bone marrow-conditioned medium. Substantial AGR-2 expression was also confirmed in prostate cancer tissue specimens in patients with bone lesions. By developing stable clones of PC3 cells with varying levels of AGR-2 expression, we identified that abrogation of AGR-2 significantly reduced cellular attachment to fibronectin, collagen I, collagen IV, laminin I and fibrinogen. Loss of cellular adhesion was associated with sharp decrease in the expression of α4, α5, αV, β3 and β4 integrins. Failure to undergo apoptosis following detachment is a hallmark of epithelial cancer metastasis. The AGR-2-silenced PC3 cells showed higher resistance to Tumor necrosis factor-related apoptosis- inducing ligand (TRAIL) induced apoptosis in vitro. This observation was also supported by significantly reduced Caspase-3 expression in AGR-2-silenced PC3 cells, which is a key effector of both extrinsic and intrinsic death signaling pathways. These data suggest that AGR-2 influence prostate cancer metastasis by regulation of cellular adhesion and apoptosis.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Diptiman
authors.initials: D
authors.lastname: Chanda
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Joo Hyoung
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Anandi
authors.initials: A
authors.lastname: Sawant
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Hensel
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Isayeva
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Reilly
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Gene P
authors.initials: GP
authors.lastname: Siegal
authors.affiliation: Hospital Laboratories, University of Alabama Hospital, Birmingham, Alabama, United States of America.
authors.forename: Claire
authors.initials: C
authors.lastname: Smith
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: William
authors.initials: W
authors.lastname: Grizzle
authors.affiliation: Vivo Biosciences Inc., Birmingham, Alabama, United States of America.
authors.forename: Raj
authors.initials: R
authors.lastname: Singh
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Selvarangan
authors.initials: S
authors.lastname: Ponnazhagan
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D016000:Cluster Analysis; D015870:Gene Expression; D020869:Gene Expression Profiling; D020868:Gene Silencing; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D009088:Mucoproteins; D009362:Neoplasm Metastasis; D015513:Oncogene Proteins; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology
chemical_list: C502296:AGR2 protein, human; D016023:Integrins; D009088:Mucoproteins; D015513:Oncogene Proteins; D011506:Proteins; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand