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

Date

5-15-2013

Document Type

Article

Medical Subject Headings

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.

Comments

Citation: J Immunol. 2013 May 15;190(10):5216-25. doi: 10.4049/jimmunol.1300097. Link to article on publisher's site

Related Resources

Link to Article in PubMed