Small molecules targeting cGAS-STING pathway for autoimmune disease

Zhao, Jiannan; Xiao, Ruoxuan; Zeng, Ruoqing; He, Ende; Zhang, Ao

doi:10.1016/j.ejmech.2022.114480

Cited by 12 publications

(7 citation statements)

References 51 publications

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“…The induction of IFN-I signaling is essential for the immune system to eliminate cells infected with viruses and intracellular bacterial infections. During infection, the presence of foreign DNA in the cytosol leads to activation of cGAS and subsequent induction of the IFN-I response [ 53 , 55 , 56 ]. Here, we identified elevated levels of cytosolic DNA from micronuclei and mitochondria in metastatic cancer cells in sterile culture conditions.…”

Section: Discussionmentioning

confidence: 99%

Opposite and dynamic regulation of the interferon response in metastatic and non-metastatic breast cancer

et al. 2023

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Background To our current understanding, solid tumors depend on suppressed local immune reactions, often elicited by the interaction between tumor cells and tumor microenvironment (TME) components. Despite an improved understanding of anti-cancer immune responses in the TME, it is still unclear how immuno-suppressive TME are formed and how some cancer cells survive and metastasize. Methods To identify the major adaptations that cancer cells undergo during tumor development and progression, we compared the transcriptome and proteome from metastatic 66cl4 and non-metastatic 67NR cell lines in culture versus their corresponding mouse mammary primary tumors. Using confocal microscopy, RT-qPCR, flow cytometry and western blotting, we studied the signaling pathway and the mechanisms involved. In addition, we used public gene expression data from human breast cancer biopsies to evaluate the correlation between gene expression and clinical outcomes in patients. Results We found that type I interferon (IFN-I) response was a key differentially regulated pathway between metastatic and non-metastatic cell lines and tumors. The IFN-I response was active in metastatic cancer cells in culture and markedly dampened when these cells formed primary tumors. Interestingly, the opposite was observed in non-metastatic cancer cells and tumors. Consistent with an active IFN-I response in culture, the metastatic cancer cells displayed elevated levels of cytosolic DNA from both mitochondria and ruptured micronuclei with concomitant activation of cGAS-STING signaling. Interestingly, decreased IFN-I-related gene expression in breast cancer biopsies correlated with an unfavourable prognosis in patients. Conclusion Our findings show that IFN-I response is dampened in the tumors with the metastatic ability and lower IFN-I expression predicts poor prognosis in triple-negative and HER2 enriched breast cancer patients. This study highlights the possibility of reactivating the IFN-I response as a potential therapeutic strategy in breast cancer. Graphical abstract

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Section: Discussionmentioning

confidence: 99%

Opposite and dynamic regulation of the interferon response in metastatic and non-metastatic breast cancer

et al. 2023

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“…In terms of STING inhibitors, nitro fatty acids (NO2-FAs) have been shown to inhibit the production of IFN-I in fibroblasts of SAVI patients ( Hansen et al., 2018a ). Palbociclib can reduce the inflammatory response and tissue damage in a DSS-induced mouse models of colitis ( Vinogradova et al., 2020 ; Zhao et al., 2022 ). Thus, inhibitors targeting cGAS and STING deserve further study in the treatment of autoimmune inflammatory diseases caused by abnormal activation of the pathway.…”

Section: Therapeutic Drugs Targeting Cgas and Stingmentioning

confidence: 99%

“…Many drugs and inhibitors targeting cGAS and STING have been developed for the treatment of inflammatory-related diseases and tumors ( Zhao et al., 2022 ). However, the “double-edged sword” effects of cGAS-STING signaling during tumorigenesis and tumor therapy limit their effectiveness and reliability ( Klarquist et al., 2014 ; Li & Chen, 2018 ; Wang et al., 2017a ).…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Current understanding of the cGAS-STING signaling pathway: Structure, regulatory mechanisms, and related diseases

Pan

Fei

et al. 2023

Zoological Research

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The innate immune system protects the host from external pathogens and internal damage in various ways. The cGAS-STING signaling pathway, comprised of cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), and downstream signaling adaptors, plays an essential role in protective immune defense against microbial DNA and internal damaged-associated DNA and is responsible for various immune-related diseases. After binding with DNA, cytosolic cGAS undergoes conformational change and DNA-linked liquid-liquid phase separation to produce 2'3'-cGAMP for the activation of endoplasmic reticulum (ER)-localized STING. However, further studies revealed that cGAS is predominantly expressed in the nucleus and strictly tethered to chromatin to prevent binding with nuclear DNA, and functions differently from cytosolic-localized cGAS. Detailed delineation of this pathway, including its structure, signaling, and regulatory mechanisms, is of great significance to fully understand the diversity of cGAS-STING activation and signaling and will be of benefit for the treatment of inflammatory diseases and cancer. Here, we review recent progress on the above-mentioned perspectives of the cGAS-STING signaling pathway and discuss new avenues for further study.

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“…Vinogradova et al identified a series of compounds named BPK as STING inhibitors that reduced cGAMP-induced STING activation [ 104 ]. It was proven in silico that the binding sites of these compounds are associated with STING C91, the same as C-178 [ 1 , 104 ]. However, it should be noted that BPK-21 and BPK-25 have limited specificity and can also interact with the cysteine residues of other immune-related proteins.…”

Section: Sting Inhibitorsmentioning

confidence: 99%

“…Type I interferons (IFNs), a kind of cytokines mainly secreted by the activated innate immune system, can further activate immune cells and boost host immunity. Pattern recognition receptors (PRRs) are indispensable to innate immune cells and can recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) [ 1 ]; upon detection by PRRs, PAMPs, or DAMPs, they activate proinflammatory signaling pathways, release inflammatory factors, and initiate adaptive immunity. PRRs signaling can be regulated by multiple pathways in order to eliminate microorganisms promptly and maintain the proper immune response to avoid adverse effects [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Potential Therapeutic Value of the STING Inhibitors

2023

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The stimulator of interferon genes (STING) is a critical protein in the activation of the immune system in response to DNA. It can participate the inflammatory response process by modulating the inflammation-preferred translation program through the STING-PKR-like endoplasmic reticulum kinase (PERK)-eIF2α pathway or by inducing the secretion of type I interferons (IFNs) and a variety of proinflammatory factors through the recruitment of TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) or the regulation of the nuclear factor kappa-B (NF-κB) pathway. Based on the structure, location, function, genotype, and regulatory mechanism of STING, this review summarizes the potential value of STING inhibitors in the prevention and treatment of infectious diseases, psoriasis, systemic lupus erythematosus, non-alcoholic fatty liver disease, and other inflammatory and autoimmune diseases.

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Small molecules targeting cGAS-STING pathway for autoimmune disease

Cited by 12 publications

References 51 publications

Opposite and dynamic regulation of the interferon response in metastatic and non-metastatic breast cancer

Opposite and dynamic regulation of the interferon response in metastatic and non-metastatic breast cancer

Current understanding of the cGAS-STING signaling pathway: Structure, regulatory mechanisms, and related diseases

Potential Therapeutic Value of the STING Inhibitors

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