title: Differences and Similarities in TRAIL- and Tumor Necrosis Factor-Mediated Necroptotic Signaling in Cancer Cells.
abstract: Recently, a type of regulated necrosis (RN) called necroptosis was identified to be involved in many pathophysiological processes and emerged as an alternative method to eliminate cancer cells. However, only a few studies have elucidated components of TRAIL-mediated necroptosis useful for anticancer therapy. Therefore, we have compared this type of cell death to tumor necrosis factor (TNF)-mediated necroptosis and found similar signaling through acid and neutral sphingomyelinases, the mitochondrial serine protease HtrA2/Omi, Atg5, and vacuolar H(+)-ATPase. Notably, executive mechanisms of both TRAIL- and TNF-mediated necroptosis are independent of poly(ADP-ribose) polymerase 1 (PARP-1), and depletion of p38α increases the levels of both types of cell death. Moreover, we found differences in signaling between TNF- and TRAIL-mediated necroptosis, e.g., a lack of involvement of ubiquitin carboxyl hydrolase L1 (UCH-L1) and Atg16L1 in executive mechanisms of TRAIL-mediated necroptosis. Furthermore, we discovered indications of an altered involvement of mitochondrial components, since overexpression of the mitochondrial protein Bcl-2 protected Jurkat cells from TRAIL- and TNF-mediated necroptosis, and overexpression of Bcl-XL diminished only TRAIL-induced necroptosis in Colo357 cells. Furthermore, TRAIL does not require receptor internalization and endosome-lysosome acidification to mediate necroptosis. Taken together, pathways described for TRAIL-mediated necroptosis and differences from those for TNF-mediated necroptosis might be unique targets to increase or modify necroptotic signaling and eliminate tumor cells more specifically in future anticancer approaches.
authors.affiliation: Institut für Immunologie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany justyna.sosna@uksh.de.
authors.forename: Justyna
authors.initials: J
authors.lastname: Sosna
authors.affiliation: Institut für Immunologie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Philipp
authors.affiliation: Institut für Immunologie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
authors.forename: Johaiber
authors.initials: J
authors.lastname: Fuchslocher Chico
authors.affiliation: Institut für Immunologie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
authors.forename: Carina
authors.initials: C
authors.lastname: Saggau
authors.affiliation: Institut für Immunologie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Fritsch
authors.affiliation: Institut für Immunologie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Föll
authors.affiliation: Institut für Immunologie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Plenge
authors.affiliation: Institut für Chemie der Humboldt-Universität, Berlin, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Arenz
authors.affiliation: Institut für Chemie der Humboldt-Universität, Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Pinkert
authors.affiliation: Institut für Experimentelle Tumorforschung, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Kalthoff
authors.affiliation: Institut für Experimentelle Tumorforschung, Christian-Albrechts-Universität zu Kiel, Kiel, Germany Klinik für Allgemeine Chirurgie, Viszeral-, Thorax-, Transplantations- und Kinderchirurgie, Universitätsklinikum Schleswig-Holstein, Kiel, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Trauzold
authors.affiliation: Systemorientierte Immunologie und Entzündungsforschung, Institut für Molekulare und Klinische Immunologie, Otto von Guericke Universität Magdeburg, Helmholtz Zentrum für Infektionsforschung, Braunschweig, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Schmitz
authors.affiliation: Institut für Immunologie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Schütze
authors.affiliation: Institut für Immunologie, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Adam
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D019073:HT29 Cells; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009336:Necrosis; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D048069:Tumor Necrosis Factors / Q000378:metabolism*
chemical_list: D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D048069:Tumor Necrosis Factors