title: Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics.
abstract: Birinapant is a smac-mimetic (SM) in clinical trials for treating cancer. SM antagonize inhibitor of apoptosis (IAP) proteins and simultaneously induce tumor necrosis factor (TNF) secretion to render cancers sensitive to TNF-induced killing. To enhance SM efficacy, we screened kinase inhibitors for their ability to increase TNF production of SM-treated cells. We showed that p38 inhibitors increased TNF induced by SM. Unexpectedly, even though p38 is required for Toll-like receptors to induce TNF, loss of p38 or its downstream kinase MK2 increased induction of TNF by SM. Hence, we show that the p38/MK2 axis can inhibit or promote TNF production, depending on the stimulus. Importantly, clinical p38 inhibitors overcame resistance of primary acute myeloid leukemia to birinapant.
authors: Cell Signaling & Cell Death and Cancer & Hematology Divisions, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors: Najoua
authors: N
authors: Lalaoui
authors: Institute of Experimental Immunology, University of Zürich, Zürich 8057, Switzerland.
authors: Kay
authors: K
authors: Hänggi
authors: Cell Signaling & Cell Death and Cancer & Hematology Divisions, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors: Gabriela
authors: G
authors: Brumatti
authors: Cell Signaling & Cell Death and Cancer & Hematology Divisions, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors: Diep
authors: D
authors: Chau
authors: Department of Clinical Hematology, The Alfred Hospital and Monash University, Melbourne, VIC 3004, Australia; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3004, Australia.
authors: Nhu-Y N
authors: NY
authors: Nguyen
authors: Institute of Experimental Immunology, University of Zürich, Zürich 8057, Switzerland.
authors: Lazaros
authors: L
authors: Vasilikos
authors: Institute of Experimental Immunology, University of Zürich, Zürich 8057, Switzerland.
authors: Lisanne M
authors: LM
authors: Spilgies
authors: Cell Signaling & Cell Death and Cancer & Hematology Divisions, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors: Denise A
authors: DA
authors: Heckmann
authors: Cell Signaling & Cell Death and Cancer & Hematology Divisions, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors: Chunyan
authors: C
authors: Ma
authors: Gene Regulation Laboratory, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3050, Australia.
authors: Margherita
authors: M
authors: Ghisi
authors: Gene Regulation Laboratory, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3050, Australia.
authors: Jessica M
authors: JM
authors: Salmon
authors: Gene Regulation Laboratory, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3050, Australia.
authors: Geoffrey M
authors: GM
authors: Matthews
authors: Immunomonitoring Facility and Centre for Biomedical Research, The Burnet Institute, Melbourne, VIC 3004, Australia; Department of Immunology, Central Clinical School, Monash University, Melbourne, VIC 3181, Australia.
authors: Elisha
authors: E
authors: de Valle
authors: Department of Clinical Hematology, The Alfred Hospital and Monash University, Melbourne, VIC 3004, Australia; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3004, Australia.
authors: Donia M
authors: DM
authors: Moujalled
authors: Institute of Physiological Chemistry, Hannover Medical School, Carl-Neuberg-Street 1, 30625 Hannover, Germany.
authors: Manoj B
authors: MB
authors: Menon
authors: Cell Signaling & Cell Death and Cancer & Hematology Divisions, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors: Sukhdeep Kaur
authors: SK
authors: Spall
authors: Cell Signaling & Cell Death and Cancer & Hematology Divisions, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors: Stefan P
authors: SP
authors: Glaser
authors: Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Randwick, NSW 2031, Australia.
authors: Jennifer
authors: J
authors: Richmond
authors: Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Randwick, NSW 2031, Australia.
authors: Richard B
authors: RB
authors: Lock
authors: TetraLogic Pharmaceuticals Corporation, 343 Phoenixville Pike, Malvern, PA 19355, USA.
authors: Stephen M
authors: SM
authors: Condon
authors: Immunomonitoring Facility and Centre for Biomedical Research, The Burnet Institute, Melbourne, VIC 3004, Australia; Department of Immunology, Central Clinical School, Monash University, Melbourne, VIC 3181, Australia.
authors: Raffi
authors: R
authors: Gugasyan
authors: Institute of Physiological Chemistry, Hannover Medical School, Carl-Neuberg-Street 1, 30625 Hannover, Germany.
authors: Matthias
authors: M
authors: Gaestel
authors: Department of Clinical Hematology, The Alfred Hospital and Monash University, Melbourne, VIC 3004, Australia; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3004, Australia.
authors: Mark
authors: M
authors: Guthridge
authors: Gene Regulation Laboratory, Cancer Therapeutics Program, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3050, Australia.
authors: Ricky W
authors: RW
authors: Johnstone
authors: Department of Pathology, School of Medical Sciences, University of Sydney, Sydney, NSW 2006, Australia.
authors: Lenka
authors: L
authors: Munoz
authors: Department of Clinical Hematology, The Alfred Hospital and Monash University, Melbourne, VIC 3004, Australia; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3004, Australia.
authors: Andrew
authors: A
authors: Wei
authors: Cell Signaling & Cell Death and Cancer & Hematology Divisions, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Pediatrics, University of Melbourne, Parkville, VIC 3050, Australia; Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia.
authors: Paul G
authors: PG
authors: Ekert
authors: Cell Signaling & Cell Death and Cancer & Hematology Divisions, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia.
authors: David L
authors: DL
authors: Vaux
authors: Institute of Experimental Immunology, University of Zürich, Zürich 8057, Switzerland.
authors: W Wei-Lynn
authors: WW
authors: Wong
authors: Cell Signaling & Cell Death and Cancer & Hematology Divisions, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3050, Australia. Electronic address: silke@wehi.edu.au.
authors: John
authors: J
authors: Silke
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051017:Apoptosis Regulatory Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D007938:Leukemia / Q000188:drug therapy*; D051379:Mice; D024101:Mitochondrial Proteins / Q000502:physiology*; D018716:Molecular Mimicry; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D017346:Protein Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C412403:DIABLO protein, human