Smac mimetics and type II interferon synergistically induce necroptosis in various cancer cell lines

被引:32
作者
Cekay, Michael John [1 ]
Roesler, Stefanie [1 ]
Frank, Tanja [1 ]
Knuth, Anne-Kathrin [1 ]
Eckhardt, Ines [1 ,2 ,3 ]
Fulda, Simone [1 ,2 ,3 ]
机构
[1] Goethe Univ, Inst Expt Canc Res Pediat, Komturstr 3a, D-60528 Frankfurt, Germany
[2] German Canc Consortium DKFK, Partner Site Frankfurt, Frankfurt, Germany
[3] German Canc Res Ctr, Heidelberg, Germany
关键词
Cell death; Necroptosis; Smac; Interferon; Cancer; BYPASSES APOPTOSIS RESISTANCE; CARCINOMA-CELLS; ALPHA; ACTIVATION; DEATH; NECROSIS;
D O I
10.1016/j.canlet.2017.09.002
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Since cancer cells often evade apoptosis, induction of necroptosis as another mode of programmed cell death is considered a promising therapeutic alternative. Here, we identify a novel synergistic interaction of Smac mimetics that antagonize x-linked Inhibitor of Apoptosis (XIAP), cellular Inhibitor of Apoptosis (cIAP) 1 and 2 with interferon (IFN)gamma to induce necroptosis in apoptosis-resistant cancer cells in which caspase activation is blocked. This synergism is confirmed by calculation of combination indices (CIs) and found in both solid and hematological cancer cell lines as well as for different Smac mimetics (i.e. BV6, Birinapant), pointing to a broader relevance. Importantly, individual genetic knockdown of key components of necroptosis signaling, i.e. receptor-interacting protein (RIP) 1, RIP3 or mixed lineage kinase domain-like pseudokinase (MLKL), significantly protects from BV6/IFN gamma-induced cell death. Similarly, pharmacological inhibitors of RIP1 (necrostatin-1(Nec-1)), RIP3 (GSK'872) or MLKL (necrosulfonamide (NSA)) significantly reduce BV6/IFN gamma-stimulated cell death. Of note, IFN-regulatory factor (IRF)1 is required for BV6/IFN gamma-mediated necroptosis, as IRF1 silencing provides protection from cell death. By comparison, antibodies blocking tumor necrosis factor (TNF)alpha, TNF-related apoptosis-inducing ligand (TRAIL) or CD95 ligand fail to inhibit BV6/IFN gamma-induced cell death, pointing to a mechanism independently of death receptor ligands. This is the first report showing that Smac mimetics synergize with IFN gamma to trigger necroptosis in apoptosis-resistant cancer cells with important implications for Smac mimetic based strategies for the treatment of cancer. (C) 2017 Elsevier B.V. All rights reserved.
引用
收藏
页码:228 / 237
页数:10
相关论文
共 31 条
[1]   Synergistic interaction of Smac mimetic and IFNα to trigger apoptosis in acute myeloid leukemia cells [J].
Bake, Vanessa ;
Roesler, Stefanie ;
Eckhardt, Ines ;
Belz, Katharina ;
Fulda, Simone .
CANCER LETTERS, 2014, 355 (02) :224-231
[2]   Smac mimetic and glucocorticoids synergize to induce apoptosis in childhood ALL by promoting ripoptosome assembly [J].
Belz, Katharina ;
Schoeneberger, Hannah ;
Wehner, Sibylle ;
Weigert, Andreas ;
Boenig, Halvard ;
Klingebiel, Thomas ;
Fichtner, Iduna ;
Fulda, Simone .
BLOOD, 2014, 124 (02) :240-250
[3]   Smac mimetics synergize with immune checkpoint inhibitors to promote tumour immunity against glioblastoma [J].
Beug, Shawn T. ;
Beauregard, Caroline E. ;
Healy, Cristin ;
Sanda, Tarun ;
St-Jean, Martine ;
Chabot, Janelle ;
Walker, Danielle E. ;
Mohan, Aditya ;
Earl, Nathalie ;
Lun, Xueqing ;
Senger, Donna L. ;
Robbins, Stephen M. ;
Staeheli, Peter ;
Forsyth, Peter A. ;
Alain, Tommy ;
LaCasse, Eric C. ;
Korneluk, Robert G. .
NATURE COMMUNICATIONS, 2017, 8
[4]   Drug Combination Studies and Their Synergy Quantification Using the Chou-Talalay Method [J].
Chou, Ting-Chao .
CANCER RESEARCH, 2010, 70 (02) :440-446
[5]   MLKL Compromises Plasma Membrane Integrity by Binding to Phosphatidylinositol Phosphates [J].
Dondelinger, Yves ;
Declercq, Wim ;
Montessuit, Sylvie ;
Roelandt, Ria ;
Goncalves, Amanda ;
Bruggeman, Inge ;
Hulpiau, Paco ;
Weber, Kathrin ;
Sehon, Clark A. ;
Marquis, Robert W. ;
Bertin, John ;
Gough, Peter J. ;
Savvides, Savvas ;
Martinou, Jean-Claude ;
Bertrand, Mathieu J. M. ;
Vandenabeele, Peter .
CELL REPORTS, 2014, 7 (04) :971-981
[6]   Identification of IRF1 as critical dual regulator of Smac mimetic-induced apoptosis and inflammatory cytokine response [J].
Eckhardt, I. ;
Weigert, A. ;
Fulda, S. .
CELL DEATH & DISEASE, 2014, 5 :e1562-e1562
[7]   Identification of DR5 as a critical, NF-κB-regulated mediator of Smac-induced apoptosis [J].
Eckhardt, I. ;
Roesler, S. ;
Fulda, S. .
CELL DEATH & DISEASE, 2013, 4 :e936-e936
[8]   Functional CD95 Ligand and CD95 death-inducing signaling complex in activation-induced cell death and doxorubicin-induced apoptosis in leukemic T cells [J].
Fulda, S ;
Strauss, G ;
Meyer, E ;
Debatin, KM .
BLOOD, 2000, 95 (01) :301-308
[9]   Promises and Challenges of Smac Mimetics as Cancer Therapeutics [J].
Fulda, Simone .
CLINICAL CANCER RESEARCH, 2015, 21 (22) :5030-5036
[10]   Therapeutic exploitation of necroptosis for cancer therapy [J].
Fulda, Simone .
SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY, 2014, 35 :51-56