University of Massachusetts Medical School Faculty Publications
Title
Mouse, but not Human STING, Binds and Signals in Response to the Vascular Disrupting Agent 5,6-Dimethylxanthenone-4-Acetic Acid
UMMS Affiliation
Department of Medicine, Division of Infectious Diseases and Immunology
Publication Date
2013-05-15
Document Type
Article
Subjects
Membrane Proteins; Adaptor Proteins, Signal Transducing; Xanthones
Disciplines
Cancer Biology | Immunology and Infectious Disease
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.
DOI of Published Version
10.4049/jimmunol.1300097
Source
J Immunol. 2013 May 15;190(10):5216-25. doi: 10.4049/jimmunol.1300097. Link to article on publisher's site
Related Resources
Journal/Book/Conference Title
Journal of immunology (Baltimore, Md. : 1950)
PubMed ID
23585680
Repository Citation
Conlon, Joseph E.; Burdette, Dara; Sharma, Shrutie; Bhat, Numana; Thompson, Mikayla R.; Jiang, Zhaozhao; Rathinam, Vijay A. K.; Monks, Brian G.; Jin, Tengchuan; Xiao, T. Sam; Vogel, Stefanie N.; Vance, Russell E.; and Fitzgerald, Katherine A., "Mouse, but not Human STING, Binds and Signals in Response to the Vascular Disrupting Agent 5,6-Dimethylxanthenone-4-Acetic Acid" (2013). University of Massachusetts Medical School Faculty Publications. 17.
https://escholarship.umassmed.edu/faculty_pubs/17