title: Mouse, but not human STING, binds and signals in response to the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid.
abstract: 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.
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Conlon
authors.forename: Dara L
authors.initials: DL
authors.lastname: Burdette
authors.forename: Shruti
authors.initials: S
authors.lastname: Sharma
authors.forename: Numana
authors.initials: N
authors.lastname: Bhat
authors.forename: Mikayla
authors.initials: M
authors.lastname: Thompson
authors.forename: Zhaozhao
authors.initials: Z
authors.lastname: Jiang
authors.forename: Vijay A K
authors.initials: VA
authors.lastname: Rathinam
authors.forename: Brian
authors.initials: B
authors.lastname: Monks
authors.forename: Tengchuan
authors.initials: T
authors.lastname: Jin
authors.forename: T Sam
authors.initials: TS
authors.lastname: Xiao
authors.forename: Stefanie N
authors.initials: SN
authors.lastname: Vogel
authors.forename: Russell E
authors.initials: RE
authors.lastname: Vance
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D016899:Interferon-beta / Q000187:drug effects / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D044004:Xanthones / Q000378:metabolism* / Q000494:pharmacology*; D000099197:STING Protein
chemical_list: D000970:Antineoplastic Agents; D050838:Interferon Regulatory Factor-3; D016899:Interferon-beta; D008565:Membrane Proteins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D044004:Xanthones; C532857:STING1 protein, human; D000099197:STING Protein; C530855:Sting1 protein, mouse; C066668:vadimezan; C498588:Tbk1 protein, mouse