title: Inhibition of renalase expression and signaling has antitumor activity in pancreatic cancer.
abstract: An essential feature of cancer is dysregulation of cell senescence and death. Renalase, a recently discovered secreted flavoprotein, provides cytoprotection against ischemic and toxic cellular injury by signaling through the PI3K-AKT and MAPK pathways. Here we show that renalase expression is increased in pancreatic cancer tissue and that it functions as a growth factor. In a cohort of patients with pancreatic ductal adenocarcinoma, overall survival was inversely correlated with renalase expression in the tumor mass, suggesting a pathogenic role for renalase. Inhibition of renalase signaling using siRNA or inhibitory anti-renalase antibodies decreased the viability of cultured pancreatic ductal adenocarcinoma cells. In two xenograft mouse models, either the renalase monoclonal antibody m28-RNLS or shRNA knockdown of renalase inhibited pancreatic ductal adenocarcinoma growth. Inhibition of renalase caused tumor cell apoptosis and cell cycle arrest. These results reveal a previously unrecognized role for the renalase in cancer: its expression may serve as a prognostic maker and its inhibition may provide an attractive therapeutic target in pancreatic cancer.
authors.affiliation: Department of Medicine, VACHS, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Xiaojia
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Medicine, VACHS, Yale University School of Medicine, New Haven, CT 06520, USA.|Department of Surgery, University of Connecticut, Farmington, CT 06032, USA.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Hollander
authors.affiliation: Department of Medicine, VACHS, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: MacPherson
authors.affiliation: Renal Division, Renji hospital, Shanghai Jiaotong Univ School of Medicine, Shanghai, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Medicine, VACHS, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Heino
authors.initials: H
authors.lastname: Velazquez
authors.affiliation: Department of Medicine, VACHS, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: John
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Medicine, VACHS, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Safirstein
authors.affiliation: Department of Surgery, VACHS, Yale University, New Haven, CT 06520, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Cha
authors.affiliation: Department of Medicine, VACHS, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Fred
authors.initials: F
authors.lastname: Gorelick
authors.affiliation: Department of Medicine, VACHS, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Gary V
authors.initials: GV
authors.lastname: Desir
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D008995:Monoamine Oxidase / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000906:Antibodies; D008995:Monoamine Oxidase; C521557:renalase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt