title: HuR Contributes to TRAIL Resistance by Restricting Death Receptor 4 Expression in Pancreatic Cancer Cells.
abstract: Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal cancers, in part, due to resistance to both conventional and targeted therapeutics. TRAIL directly induces apoptosis through engagement of cell surface Death Receptors (DR4 and DR5), and has been explored as a molecular target for cancer treatment. Clinical trials with recombinant TRAIL and DR-targeting agents, however, have failed to show overall positive outcomes. Herein, we identify a novel TRAIL resistance mechanism governed by Hu antigen R (HuR, ELAV1), a stress-response protein abundant and functional in PDA cells. Exogenous HuR overexpression in TRAIL-sensitive PDA cell lines increases TRAIL resistance whereas silencing HuR in TRAIL-resistant PDA cells, by siRNA oligo-transfection, decreases TRAIL resistance. PDA cell exposure to soluble TRAIL induces HuR translocation from the nucleus to the cytoplasm. Furthermore, it is demonstrated that HuR interacts with the 3'-untranslated region (UTR) of DR4 mRNA. Pre-treatment of PDA cells with MS-444 (Novartis), an established small molecule inhibitor of HuR, substantially increased DR4 and DR5 cell surface levels and enhanced TRAIL sensitivity, further validating HuR's role in affecting TRAIL apoptotic resistance. NanoString analyses on the transcriptome of TRAIL-exposed PDA cells identified global HuR-mediated increases in antiapoptotic processes. Taken together, these data extend HuR's role as a key regulator of TRAIL-induced apoptosis.
  
  
  
  Discovery of an important new HuR-mediated TRAIL resistance mechanism suggests that tumor-targeted HuR inhibition increases sensitivity to TRAIL-based therapeutics and supports their re-evaluation as an effective treatment for PDA patients. Mol Cancer Res; 14(7); 599-611. ©2016 AACR.
authors.affiliation: Division of Surgical Research, Department of Surgery, Jefferson Pancreas, Biliary, and Related Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania. Department of Pathology, Anatomy, and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Carmella
authors.initials: C
authors.lastname: Romeo
authors.affiliation: Department of Pathology, Anatomy, and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Weber
authors.affiliation: Division of Surgical Research, Department of Surgery, Jefferson Pancreas, Biliary, and Related Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Mahsa
authors.initials: M
authors.lastname: Zarei
authors.affiliation: Department of Pathology, Anatomy, and Cell Biology, Daniel Baugh Institute, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Danielle
authors.initials: D
authors.lastname: DeCicco
authors.affiliation: Division of Surgical Research, Department of Surgery, Jefferson Pancreas, Biliary, and Related Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Saswati N
authors.initials: SN
authors.lastname: Chand
authors.affiliation: Department of Pathology, Anatomy, and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Angie D
authors.initials: AD
authors.lastname: Lobo
authors.affiliation: Division of Surgical Research, Department of Surgery, Jefferson Pancreas, Biliary, and Related Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Jordan M
authors.initials: JM
authors.lastname: Winter
authors.affiliation: Lankenau Institute for Medical Research, Wynnewood, Pennsylvania.
authors.forename: Janet A
authors.initials: JA
authors.lastname: Sawicki
authors.affiliation: Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Sachs
authors.affiliation: Novartis Institutes for Biomedical Research, Novartis, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Meisner-Kober
authors.affiliation: Division of Surgical Research, Department of Surgery, Jefferson Pancreas, Biliary, and Related Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Yeo
authors.affiliation: Department of Pathology, Anatomy, and Cell Biology, Daniel Baugh Institute, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Rajanikanth
authors.initials: R
authors.lastname: Vadigepalli
authors.affiliation: Department of Pathology, Anatomy, and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Tykocinski
authors.affiliation: Division of Surgical Research, Department of Surgery, Jefferson Pancreas, Biliary, and Related Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania. jonathan.brody@jefferson.edu.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Brody
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D000067780:ELAV-Like Protein 1 / Q000378:metabolism*; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014162:Transfection
chemical_list: D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505653:TNFSF10 protein, human