STING enhances cell death through regulation of reactive oxygen species and DNA damage
| Autor: | Wei Cui, David L. Rimm, Kevin Leach, Thazin Nwe Aung, Radhakrishnan P. Iyer, Sreerupa Challa, Barbara Burtness, Thomas J. Hayman, Chatchai Phoomak, Tyler MacNeil, Joseph N. Contessa, Marta Baro, Teresa Sandoval-Schaefer |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Programmed cell death DNA damage Science Regulator Mice Nude General Physics and Astronomy Double-strand DNA breaks Kaplan-Meier Estimate Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Animals Humans Medicine Head and neck cancer chemistry.chemical_classification Regulation of gene expression Reactive oxygen species Multidisciplinary Radiotherapy Squamous Cell Carcinoma of Head and Neck business.industry HEK 293 cells Membrane Proteins General Chemistry Xenograft Model Antitumor Assays eye diseases Gene Expression Regulation Neoplastic Mice Inbred C57BL Sting HEK293 Cells 030104 developmental biology chemistry 030220 oncology & carcinogenesis Stimulator of interferon genes Cancer research Female Reactive Oxygen Species business DNA Damage |
| Zdroj: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-14 (2021) |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-021-22572-8 |
| Popis: | Resistance to DNA-damaging agents is a significant cause of treatment failure and poor outcomes in oncology. To identify unrecognized regulators of cell survival we performed a whole-genome CRISPR-Cas9 screen using treatment with ionizing radiation as a selective pressure, and identified STING (stimulator of interferon genes) as an intrinsic regulator of tumor cell survival. We show that STING regulates a transcriptional program that controls the generation of reactive oxygen species (ROS), and that STING loss alters ROS homeostasis to reduce DNA damage and to cause therapeutic resistance. In agreement with these data, analysis of tumors from head and neck squamous cell carcinoma patient specimens show that low STING expression is associated with worse outcomes. We also demonstrate that pharmacologic activation of STING enhances the effects of ionizing radiation in vivo, providing a rationale for therapeutic combinations of STING agonists and DNA-damaging agents. These results highlight a role for STING that is beyond its canonical function in cyclic dinucleotide and DNA damage sensing, and identify STING as a regulator of cellular ROS homeostasis and tumor cell susceptibility to reactive oxygen dependent, DNA damaging agents. The endoplasmic reticulum-localized adaptor STING regulates the innate immune response through its ability to sense DNA damage. Here the authors reveal that STING functions as a regulator of cellular ROS homeostasis and tumor cell susceptibility to reactive oxygen dependent, DNA damaging agents. |
| Databáze: | OpenAIRE |
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