title: Second mitochondria-derived activator of caspase (SMAC) mimetic potentiates tumor susceptibility toward natural killer cell-mediated killing.
abstract: Resistance to apoptosis is a hallmark of cancer, and represents an important mechanism of how tumor cells resist immune cell destruction. Mitochondria are the central regulators of the apoptotic machinery by releasing pro-apoptotic factors including cytochrome c and second mitochondria-derived activator of caspase (SMAC) upon mitochondrial outer membrane permeabilization (MOMP). Small molecules activating MOMP such as BH3 mimetics or antagonizers of the inhibitor of apoptosis proteins (IAPs) such as SMAC mimetics have recently engendered new optimism for a more individualized and effective cancer therapy. Here we show that a SMAC mimetic potentiates cancer cell killing by natural killer (NK) cells through reactivation of tumor cell apoptosis. Specifically, the SMAC mimetic enhances the susceptibility of tumor cells toward NK cell-mediated effector mechanisms involving death receptors and cytolytic granules containing perforin and granzymes by relieving caspase activity. Our data highlight for the first time the specific use of SMAC mimetics for boosting immune cell-mediated immunotherapy, representing a novel and promising approach in the treatment of cancer.
authors.affiliation: Center for Molecular Medicine Cologne (CMMC), Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Institute for Medical Microbiology, Immunology and Hygiene (IMMIH), University of Cologne , Cologne , Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Brinkmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Hombach
authors.forename: Jens Michael
authors.initials: JM
authors.lastname: Seeger
authors.forename: Diana
authors.initials: D
authors.lastname: Wagner-Stippich
authors.forename: Daniela
authors.initials: D
authors.lastname: Klubertz
authors.forename: Martin
authors.initials: M
authors.lastname: Krönke
authors.forename: Hinrich
authors.initials: H
authors.lastname: Abken
authors.forename: Hamid
authors.initials: H
authors.lastname: Kashkar
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism*; D054353:Perforin / Q000378:metabolism; D053218:Receptors, Death Domain / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D053218:Receptors, Death Domain; D054353:Perforin; D053804:Granzymes