title: SK053 triggers tumor cells apoptosis by oxidative stress-mediated endoplasmic reticulum stress.
abstract: Thioredoxins (Trx) together with thioredoxin reductases (TrxR) participate in the maintenance of protein thiol homeostasis and play cytoprotective roles in tumor cells. Therefore, thioredoxin-thioredoxin reductase system is considered to be a promising therapeutic target in cancer treatment. We have previously reported that SK053, a peptidomimetic compound targeting the thioredoxin-thioredoxin reductase system, induces oxidative stress and demonstrates antitumor activity in mice. In this study, we investigated the mechanisms of SK053-mediated tumor cell death. Our results indicate that SK053 induces apoptosis of Raji cells accompanied by the activation of the endoplasmic reticulum (ER) stress and induction of unfolded protein response. Incubation of tumor cells with SK053 induces increase in BiP, CHOP, and spliced XBP-1 levels, which precede induction of apoptosis. CHOP-deficient (CHOP(-/-)) mouse embryonic fibroblasts are more resistant to SK053-induced apoptosis as compared with normal fibroblasts indicating that the apoptosis of tumor cells depends on the expression of this transcription factor. Additionally, the ER-stress-induced apoptosis, caused by SK053, is strongly related with Trx expression levels. Altogether, our results indicate that SK053 induces ER stress-associated apoptosis and reveal a link between thioredoxin inhibition and induction of UPR in tumor cells.
authors.affiliation: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland.
authors.forename: Angelika
authors.initials: A
authors.lastname: Muchowicz
authors.affiliation: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Firczuk
authors.affiliation: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Wachowska
authors.affiliation: Department of Histology and Embryology, Center of Biostructure Research, Medical University of Warsaw, 02-004 Warsaw, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Kujawa
authors.affiliation: Department of Histology and Embryology, Center of Biostructure Research, Medical University of Warsaw, 02-004 Warsaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Jankowska-Steifer
authors.affiliation: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Gabrysiak
authors.affiliation: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland.
authors.forename: Zofia
authors.initials: Z
authors.lastname: Pilch
authors.affiliation: Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland.
authors.forename: Szymon
authors.initials: S
authors.lastname: Kłossowski
authors.affiliation: Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland.
authors.forename: Ryszard
authors.initials: R
authors.lastname: Ostaszewski
authors.affiliation: Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1A, 02-097 Warsaw, Poland. Electronic address: jakub.golab@wum.edu.pl.
authors.forename: Jakub
authors.initials: J
authors.lastname: Golab
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002051:Burkitt Lymphoma / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D008689:Methacrylates / Q000633:toxicity*; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*
chemical_list: C570904:2,6-bis-trifluoromethylbenzoic acid 2-(1-(ethoxycarbonylmethylcarbamoyl)-3-methylbutylcarbamoyl)allyl ester; D004151:Dipeptides; D008689:Methacrylates
keywords: Apoptosis; CHOP; Cancer; Thioredoxin; Unfolded protein response