Mouse, but not Human STING, Binds and Signals in Response to the Vascular Disrupting Agent 5,6-Dimethylxanthenone-4-Acetic Acid

Vascular disrupting agents such as 5,6-dimethylxanthenone-4-acetic acid (DMXAA) represent a novel approach for cancer treatment. DMXAA has potent antitumor activity in mice and, despite significant preclinical promise, failed human clinical trials. The antitumor activity of DMXAA has been linked to its ability to induce type I IFNs in macrophages, although the molecular mechanisms involved are poorly understood. In this study, we identify stimulator of IFN gene (STING) as a direct receptor for DMXAA leading to TANK-binding kinase 1 and IFN regulatory factor 3 signaling. Remarkably, the ability to sense DMXAA was restricted to murine STING. Human STING failed to bind to or signal in response to DMXAA. Human STING also failed to signal in response to cyclic dinucleotides, conserved bacterial second messengers known to bind and activate murine STING signaling. Collectively, these findings detail an unexpected species-specific role for STING as a receptor for an anticancer drug and uncover important insights that may explain the failure of DMXAA in clinical trials for human cancer.

[1]  yang-xin fu,et al.  Type I interferon response and innate immune sensing of cancer. , 2013, Trends in immunology.

[2]  G. Cheng,et al.  DDX41 recognizes bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune response , 2012, Nature Immunology.

[3]  S. Vogel,et al.  5,6-Dimethylxanthenone-4-acetic Acid (DMXAA) Activates Stimulator of Interferon Gene (STING)-dependent Innate Immune Pathways and Is Regulated by Mitochondrial Membrane Potential* , 2012, The Journal of Biological Chemistry.

[4]  G. Cheng,et al.  Structural analysis of the STING adaptor protein reveals a hydrophobic dimer interface and mode of cyclic di-GMP binding. , 2012, Immunity.

[5]  Yuan Tian,et al.  Cyclic di-GMP sensing via the innate immune signaling protein STING. , 2012, Molecular cell.

[6]  X. Su,et al.  The structural basis for the sensing and binding of cyclic di-GMP by STING , 2012, Nature Structural &Molecular Biology.

[7]  D. Lu,et al.  Crystal structures of STING protein reveal basis for recognition of cyclic di-GMP , 2012, Nature Structural &Molecular Biology.

[8]  S. Akira,et al.  [Nucleic acids recognition by innate immunity]. , 2012, Uirusu.

[9]  C. Kao,et al.  Structure of STING bound to c-di-GMP Reveals the Mechanism of Cyclic Dinucleotide Recognition by the Immune System , 2012, Nature Structural &Molecular Biology.

[10]  Zhijian J. Chen,et al.  STING Specifies IRF3 Phosphorylation by TBK1 in the Cytosolic DNA Signaling Pathway , 2012, Science Signaling.

[11]  G. Cheng,et al.  Activation of mitogen-activated protein kinases by 5,6-dimethylxanthenone-4-acetic acid (DMXAA) plays an important role in macrophage stimulation. , 2011, Biochemical pharmacology.

[12]  Yong‐jun Liu,et al.  The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells , 2011, Nature Immunology.

[13]  G. Barber.  STING-dependent signaling , 2011, Nature Immunology.

[14]  R. Schreiber,et al.  Type I interferon is selectively required by dendritic cells for immune rejection of tumors , 2011, The Journal of experimental medicine.

[15]  Yoshihiro Hayakawa,et al.  STING is a direct innate immune sensor of cyclic-di-GMP , 2011, Nature.

[16]  Sky W. Brubaker,et al.  The N-Ethyl-N-Nitrosourea-Induced Goldenticket Mouse Mutant Reveals an Essential Function of Sting in the In Vivo Interferon Response to Listeria monocytogenes and Cyclic Dinucleotides , 2010, Infection and Immunity.

[17]  A. Bowie,et al.  IFI16 is an innate immune sensor for intracellular DNA , 2010, Nature Immunology.

[18]  M. Jameson,et al.  The development of the tumor vascular-disrupting agent ASA404 (vadimezan, DMXAA): current status and future opportunities , 2010, Expert opinion on investigational drugs.

[19]  G. Barber,et al.  STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity , 2009, Nature.

[20]  Zhijian J. Chen,et al.  RNA Polymerase III Detects Cytosolic DNA and Induces Type I Interferons through the RIG-I Pathway , 2009, Cell.

[21]  P. Dunbar,et al.  Neutrophil influx and chemokine production during the early phases of the antitumor response to the vascular disrupting agent DMXAA (ASA404). , 2009, Neoplasia.

[22]  L. Freitag,et al.  Phase II study of ASA404 (vadimezan, 5,6-dimethylxanthenone-4-acetic acid/DMXAA) 1800mg/m(2) combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer. , 2009, Lung cancer.

[23]  V. Hornung,et al.  RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III–transcribed RNA intermediate , 2009, Nature Immunology.

[24]  Jasmyn A. Dunn,et al.  HIN-200 Proteins Regulate Caspase Activation in Response to Foreign Cytoplasmic DNA , 2009, Science.

[25]  Daniel R. Caffrey,et al.  AIM2 recognizes cytosolic dsDNA and forms a caspase-1 activating inflammasome with ASC , 2009, Nature.

[26]  G. Barber,et al.  STING an Endoplasmic Reticulum Adaptor that Facilitates Innate Immune Signaling , 2008, Nature.

[27]  K. Rock,et al.  Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization , 2008, Nature Immunology.

[28]  R. Medzhitov,et al.  Role of toll-like receptors in tissue repair and tumorigenesis , 2008, Biochemistry (Moscow).

[29]  S. Vogel,et al.  IFN-beta-dependent inhibition of tumor growth by the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA). , 2008, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[30]  M. McKeage.  The potential of DMXAA (ASA404) in combination with docetaxel in advanced prostate cancer , 2008, Expert opinion on investigational drugs.

[31]  G. Cheng,et al.  The vascular disrupting agent, DMXAA, directly activates dendritic cells through a MyD88-independent mechanism and generates antitumor cytotoxic T lymphocytes. , 2007, Cancer research.

[32]  S. Akira,et al.  The chemotherapeutic agent DMXAA potently and specifically activates the TBK1–IRF-3 signaling axis , 2007, The Journal of experimental medicine.

[33]  Robert D. Schreiber,et al.  Interferons, immunity and cancer immunoediting , 2006, Nature Reviews Immunology.

[34]  P. Allavena,et al.  Role of tumor-associated macrophages in tumor progression and invasion , 2006, Cancer and Metastasis Reviews.

[35]  M. Burdick,et al.  Activation of tumor-associated macrophages by the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid induces an effective CD8+ T-cell-mediated antitumor immune response in murine models of lung cancer and mesothelioma. , 2005, Cancer research.

[36]  S. Akira,et al.  The RNA Helicase Lgp2 Inhibits TLR-Independent Sensing of Viral Replication by Retinoic Acid-Inducible Gene-I1 , 2005, The Journal of Immunology.

[37]  S. Akira,et al.  [TLR family and viral infection]. , 2004, Uirusu.

[38]  T. Maniatis,et al.  IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[39]  L. Gumbrell,et al.  Clinical aspects of a phase I trial of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent , 2003, British Journal of Cancer.

[40]  Guo-Ping Zhou,et al.  Triggering the Interferon Antiviral Response Through an IKK-Related Pathway , 2003, Science.

[41]  T. Maniatis,et al.  IKKε and TBK1 are essential components of the IRF3 signaling pathway , 2003, Nature Immunology.

[42]  B. Baguley.  Antivascular therapy of cancer: DMXAA. , 2003, The Lancet. Oncology.

[43]  H. Young,et al.  Induction of STAT and NFkappaB activation by the antitumor agents 5,6-dimethylxanthenone-4-acetic acid and flavone acetic acid in a murine macrophage cell line. , 1999, Biochemical pharmacology.

[44]  J. Sedgwick,et al.  Induction of intratumoral tumor necrosis factor (TNF) synthesis and hemorrhagic necrosis by 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in TNF knockout mice. , 1999, Cancer research.

[45]  C. Bucana,et al.  Inhibition of basic fibroblast growth factor expression, angiogenesis, and growth of human bladder carcinoma in mice by systemic interferon-alpha administration. , 1998, Cancer research.

[46]  B. Baguley,et al.  Immunomodulatory Actions of Xanthenone Anticancer Agents , 1997, BioDrugs.

[47]  C. Bucana,et al.  Interferons alpha and beta down-regulate the expression of basic fibroblast growth factor in human carcinomas. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[48]  R. Strieter,et al.  Role of C‐X‐C chemokines as regulators of angiogenesis in lung cancer , 1995, Journal of leukocyte biology.

[49]  S. Barber,et al.  Activation of LPS-inducible genes by the antitumor agent 5,6-dimethylxanthenone-4-acetic acid in primary murine macrophages. Dissection of signaling pathways leading to gene induction and tyrosine phosphorylation. , 1994, Journal of immunology.

[50]  G. P. Smith,et al.  Flavone acetic acid (NSC 347512) induces haemorrhagic necrosis of mouse colon 26 and 38 tumours. , 1987, European journal of cancer & clinical oncology.

[51]  E. Proietti,et al.  Injection of mice with antibody to interferon enhances the growth of transplantable murine tumors , 1983, The Journal of experimental medicine.

[52]  R. Medzhitov,et al.  Toll-like receptors and cancer , 2009, Nature Reviews Cancer.

[53]  L. Chamley,et al.  NF-kappaB-independent induction of endothelial cell apoptosis by the vascular disrupting agent DMXAA. , 2007, Anticancer research.

[54]  B. Baguley,et al.  Inhibition of DMXAA-induced tumor necrosis factor production in murine splenocyte cultures by NF-kappaB inhibitors. , 2006, Oncology research.

[55]  C. Kieda,et al.  A comparison of the ability of DMXAA and xanthenone analogues to activate NF-kappaB in murine and human cell lines. , 2005, Oncology research.

[56]  M. Philpott,et al.  Induction of tumour necrosis factor-α by single and repeated doses of the antitumour agent 5,6-dimethylxanthenone-4-acetic acid , 2004, Cancer Chemotherapy and Pharmacology.

[57]  G. Barber,et al.  Cellular and Molecular Life Sciences REVIEW The STING pathway and regulation of innate immune signaling in response to DNA pathogens , 2022 .