Zebularine elevates STING expression and enhances cGAMP cancer immunotherapy in mice

Lai, Junzhong; Fu, Yajuan; Tian, Shuoran; Huang, Shanlu; Luo, Xuan; Lin, Lili; Zhang, Xing; Wang, Hanze; Zhang, Lin; Zhao, Heng; Lin, Shu‐Fang; Zhao, Jin; Xu, Shan; Li, Daliang; Cai, Shaoli; Dong, Luna; Qian, Jing; Liang, Jiadi; Qiu-mei, LI; Zhang, Yong; Fan, Jiqiang; Balderas, Robert; Chen, Qi

doi:10.1016/j.ymthe.2021.02.005

Cited by 38 publications

(41 citation statements)

References 83 publications

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“…Studies have shown that 2’3’-cGAMP significantly activated immune cell as a STING pathway agonist [ 22 – 24 ]. Study has shown that Treatment to elevate STING expression enhances the cancer immunotherapy effect of cGAMP in mice [ 25 ]. Having established that the SGLT2 inhibitor activates the STING/IRF3/IFN-β pathway in osteosarcoma cells, we investigated the potential synergistic effects of the STING pathway agonist 2’3’-cGAMP and the SGLT2 inhibitor in osteosarcoma.…”

Section: Resultsmentioning

confidence: 99%

SGLT2 inhibitor activates the STING/IRF3/IFN-β pathway and induces immune infiltration in osteosarcoma

Zhang

Jing

et al. 2022

Cell Death Dis

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SGLT2 (sodium-glucose cotransporter 2) is an important mediator of epithelial glucose transport and has been reported that SGLT2, robustly and diffusely expressed in malignant cancer cells, was overexpressed in various tumors, and inhibiting the SGLT2 expression significantly inhibited tumor progression. By blocking the functional activity of SGLT2, SGLT2 inhibitors have shown anticancer effects in several malignant cancers, including breast cancer, cervical cancer, hepatocellular cancer, prostate cancer, and lung cancer. However, the anticancer effect of SGLT2 inhibitors in osteosarcoma and the specific mechanism are still unclear. In the present study, we found that SGLT2 was overexpressed at the protein level in osteosarcoma. Furthermore, our results showed that the SGLT2 inhibitor significantly inhibited osteosarcoma tumor growth and induced infiltration of immune cells in vivo by upregulating STING expression and activating the IRF3/IFN-β pathway, which could attribute to the suppression of AKT phosphorylation. In addition, the combined treatment with SGLT2 inhibitor and STING agonist 2’3’-cGAMP exerted synergistic antitumor effects in osteosarcoma. Furthermore, the overexpression of SGLT2 at the protein level was correlated with the degradation of SGLT2 induced by TRIM21. This result demonstrated that SGLT2 is a novel therapeutic target of osteosarcoma, and that the SGLT2 inhibitor, especially in combination with 2’3’-cGAMP, is a potential therapeutic drug.

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Section: Resultsmentioning

confidence: 99%

SGLT2 inhibitor activates the STING/IRF3/IFN-β pathway and induces immune infiltration in osteosarcoma

Zhang

Jing

et al. 2022

Cell Death Dis

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“…The mechanisms underlying this phenomenon have yet to be uncovered. Our group recently used zebularine (a demethylating agent) to activate the cGAS-STING signaling pathway in tumor cells (166). In our mouse tumor models, zebularine enhanced STING expression by reducing DNA methylation on the STING gene promoter.…”

Section: Discussionmentioning

confidence: 99%

“…In our mouse tumor models, zebularine enhanced STING expression by reducing DNA methylation on the STING gene promoter. Administration of zebularine alone reduced tumor burden and extended mouse survival; its combination with cGAMP or immune checkpoint inhibitors had a synergistic anti-tumor effect (166). Thus, activating the cGAS-STING signaling pathway in tumor cells can significantly enhance tumor immunotherapy effects (Figure 5).…”

Section: Discussionmentioning

confidence: 99%

A Variety of Nucleic Acid Species Are Sensed by cGAS, Implications for Its Diverse Functions

et al. 2022

Self Cite

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Cyclic GMP-AMP synthase (cGAS) recognizes double-stranded DNA (dsDNA) derived from invading pathogens and induces an interferon response via activation of the key downstream adaptor protein stimulator of interferon genes (STING). This is the most classic biological function of the cGAS-STING signaling pathway and is critical for preventing pathogenic microorganism invasion. In addition, cGAS can interact with various types of nucleic acids, including cDNA, DNA : RNA hybrids, and circular RNA, to contribute to a diverse set of biological functions. An increasing number of studies have revealed an important relationship between the cGAS-STING signaling pathway and autophagy, cellular senescence, antitumor immunity, inflammation, and autoimmune diseases. This review details the mechanism of action of cGAS as it interacts with different types of nucleic acids, its rich biological functions, and the potential for targeting this pathway to treat various diseases.

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“…Indeed, the IFN-promoting activities of ATM kinase inhibition and radiotherapy described above have been linked to their induction of mitochondrial DNA leakage, which activates tumour-intrinsic DNA sensing via cGAS/STING. 67,68 Activation of this pathway in tumour cells as well as DCs has also been achieved by epigenetic reprogramming, [69][70][71] modification of the microbiome 72 and stimulation with STING agonists, [73][74][75] each of which overcomes tumour resistance to ICB regimens in an IFN-dependent manner.…”

Section: Targeting Interferon Pathways To Counter Resistance To Immun...mentioning

confidence: 99%

The role of interferons in melanoma resistance to immune checkpoint blockade: mechanisms of escape and therapeutic implications

Hargadon

2021

Br J Dermatol

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Summary Immune checkpoint blockade (ICB) therapy has achieved unprecedented success in the treatment of metastatic melanoma, though its efficacy is often limited by innate and acquired mechanisms of resistance. Type I and type II interferons (IFNs) act as key determinants of checkpoint blockade therapeutic outcome, and tumour‐intrinsic and ‐extrinsic factors that disrupt IFN activity confer resistance to various checkpoint inhibitors. This review highlights our current understanding of the mechanisms by which tumours disrupt IFN function in the context of ICB, and it discusses therapeutic strategies to overcome these mechanisms of resistance and improve the clinical reach of ICB therapy in patients with melanoma.

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Zebularine elevates STING expression and enhances cGAMP cancer immunotherapy in mice

Cited by 38 publications

References 83 publications

SGLT2 inhibitor activates the STING/IRF3/IFN-β pathway and induces immune infiltration in osteosarcoma

SGLT2 inhibitor activates the STING/IRF3/IFN-β pathway and induces immune infiltration in osteosarcoma

A Variety of Nucleic Acid Species Are Sensed by cGAS, Implications for Its Diverse Functions

The role of interferons in melanoma resistance to immune checkpoint blockade: mechanisms of escape and therapeutic implications

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