title: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) activates caspases in human prostate cancer cells through sigma 1 receptor.
abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-based therapy is currently evaluated in clinical studies as a tumor cell-selective pro-apoptotic approach. Unfortunately, many clinical studies have shown that cancer cells acquire TRAIL resistance and finally avoid TRAIL-induced apoptosis. Therefore, defining the mechanisms that permit TRAIL to activate apoptosis is critical for the development of strategies that maximize the potential effectiveness of TRAIL in clinical applications. This study aims at understanding the molecular mechanisms underlying TRAIL-induced apoptosis and unraveling signaling pathways that could revert sensitivity to apoptosis stimuli. Our current study demonstrates for the first time that Sigma 1 Receptor (Sig1R), a ligand-regulated protein chaperone, contributes to TRAIL induction of apoptosis. We show that Sig1R agonist (+)-SKF10047 action or increasing Sig1R expression, significantly reduced apoptosis by TRAIL in prostate cell lines, indicating the importance of Sig1R and signifying that higher levels of Sig1R in prostate cancer cells make them more resistant to TRAIL treatment. Here we show that Sig1R is critically involved in TRAIL-induced caspase activation. Furthermore, we show that Sig1R protein is degraded upon TRAIL treatment. Knockdown of Sig1R, by siRNA transfection increased the sensitivity of breast cancer cells to TRAIL. These results indicate that Sig1R could represent a promising molecule to sensitize human breast cancers to TRAIL. Collectively, these studies define Sig1R as a key mediator of TRAIL induction of cancer-specific killing.
authors.affiliation: Department of Biological Sciences, Herbert H. Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, United States.
authors.forename: Dibash
authors.initials: D
authors.lastname: Das
authors.affiliation: Department of Biological Sciences, Herbert H. Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, United States.
authors.forename: Leah
authors.initials: L
authors.lastname: Persaud
authors.affiliation: Department of Biological Sciences, Herbert H. Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, United States.
authors.forename: Jordan
authors.initials: J
authors.lastname: Dejoie
authors.affiliation: Department of Biological Sciences, Herbert H. Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, United States.
authors.forename: Mireille
authors.initials: M
authors.lastname: Happy
authors.affiliation: Department of Biological Sciences, Herbert H. Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, United States.
authors.forename: Oliver
authors.initials: O
authors.lastname: Brannigan
authors.affiliation: Department of Biological Sciences, Herbert H. Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, United States.
authors.forename: Dayenny
authors.initials: D
authors.lastname: De Jesus
authors.affiliation: Department of Biological Sciences, Herbert H. Lehman College, City University of New York, 250 Bedford Park Boulevard West, Bronx, NY 10468, United States. Electronic address: moira.sauane@Lehman.cuny.edu.
authors.forename: Moira
authors.initials: M
authors.lastname: Sauane
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism*; D017480:Receptors, sigma / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000008:administration & dosage* / Q000378:metabolism*; D000097605:Sigma-1 Receptor
chemical_list: D020169:Caspases; D017480:Receptors, sigma; D053221:TNF-Related Apoptosis-Inducing Ligand; D000097605:Sigma-1 Receptor; C505653:TNFSF10 protein, human
keywords: Apoptosis; Cancer; Caspases; Sigma 1 receptor; TRAIL; Tumor necrosis factor