The chemotherapeutic agent DMXAA potently and specifically activates the TBK1–IRF-3 signaling axis

• DOI: 10.1084/jem.20061845
• Publication Date: 2007-06-12T02:32:59Z
• Authors: Zachary J. Roberts; Nadege Goutagny; Pin-Yu Perera; Hiroki Kato; Himanshu Kumar; Taro Kawai; Shizuo Akira; Ram Savan; David van Echo; Katherine A. Fitz...; Howard A. Young; Lai-Ming Ching; Stefanie N. Vogel
• Keywords: TANK-binding kinase 1

Vascular disrupting agents (VDAs) represent a novel approach to the treatment of cancer, resulting in collapse tumor vasculature and death. 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is VDA currently advanced phase II clinical trials, yet its precise mechanism action unknown despite extensive preclinical investigations. Our data demonstrate that DMXAA specific activator TANK-binding kinase 1 (TBK1)–interferon (IFN) regulatory factor 3 (IRF-3) signaling pathway. primary mouse macrophages resulted robust IRF-3 activation ∼750-fold increase IFN-β mRNA, contrast potent Toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS), was independent mitogen-activated protein (MAPK) elicited minimal nuclear κB–dependent gene expression. DMXAA-induced critically dependent on kinase, TBK1, but myeloid differentiation 88–, Toll–interleukin domain–containing adaptor inducing IFN-β–, IFN promoter-stimulator 1–, inhibitor κB kinase–independent, thus excluding all known TLRs cytosolic helicase receptors. pretreatment induced state tolerance LPS vice versa. In stimulation, dimerization expression were inhibited by salicylic acid. These findings detail pathway for TBK1-mediated provide new insights into this class chemotherapeutic drugs.