title: A Genome-Wide Loss-of-Function Screen Identifies SLC26A2 as a Novel Mediator of TRAIL Resistance.
abstract: TRAIL is a potent death-inducing ligand that mediates apoptosis through the extrinsic pathway and serves as an important endogenous tumor suppressor mechanism. Because tumor cells are often killed by TRAIL and normal cells are not, drugs that activate the TRAIL pathway have been thought to have potential clinical value. However, to date, most TRAIL-related clinical trials have largely failed due to the tumor cells having intrinsic or acquired resistance to TRAIL-induced apoptosis. Previous studies to identify resistance mechanisms have focused on targeted analysis of the canonical apoptosis pathway and other known regulators of TRAIL receptor signaling. To identify novel mechanisms of TRAIL resistance in an unbiased way, we performed a genome-wide shRNA screen for genes that regulate TRAIL sensitivity in sublines that had been selected for acquired TRAIL resistance. This screen identified previously unknown mediators of TRAIL resistance including angiotensin II receptor 2, Crk-like protein, T-Box Transcription Factor 2, and solute carrier family 26 member 2 (SLC26A2). SLC26A2 downregulates the TRAIL receptors, DR4 and DR5, and this downregulation is associated with resistance to TRAIL. Its expression is high in numerous tumor types compared with normal cells, and in breast cancer,SLC26A2is associated with a significant decrease in relapse-free survival.Implication:Our results shed light on novel resistance mechanisms that could affect the efficacy of TRAIL agonist therapies and highlight the possibility of using these proteins as biomarkers to identify TRAIL-resistant tumors, or as potential therapeutic targets in combination with TRAIL.Mol Cancer Res; 15(4); 382-94. ©2017 AACR.
authors.affiliation: Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Lina Y
authors.initials: LY
authors.lastname: Dimberg
authors.affiliation: Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Christina G
authors.initials: CG
authors.lastname: Towers
authors.affiliation: Department of Obstetrics and Gynecology, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Kian
authors.initials: K
authors.lastname: Behbakht
authors.affiliation: Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Taylor J
authors.initials: TJ
authors.lastname: Hotz
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Jihye
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology and Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Susan
authors.initials: S
authors.lastname: Fosmire
authors.affiliation: Department of Pediatrics, Division of Pediatric Hematology and Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Porter
authors.affiliation: Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Aik-Choon
authors.initials: AC
authors.lastname: Tan
authors.affiliation: Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Andrew
authors.initials: A
authors.lastname: Thorburn
authors.affiliation: Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. heide.ford@ucdenver.edu.|Department of Obstetrics and Gynecology, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Heide L
authors.initials: HL
authors.lastname: Ford
mesh_terms: D027321:Anion Transport Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D000076988:Sulfate Transporters; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D027321:Anion Transport Proteins; D034741:RNA, Small Interfering; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C089651:SLC26A2 protein, human; D000076988:Sulfate Transporters; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human