cGAS–STING drives the IL-6-dependent survival of chromosomally instable cancers

Hong, Christy; Schubert, Michaël; Tijhuis, Andréa E.; Requesens, Marta; Roorda, Maurits; Brink, Anouk van den; Ruiz, Lorena Andrade; Bakker, Petra L.; Sluis, Tineke van der; Pieters, Wietske; Chen, Mengting; Wardenaar, René; Vegt, Bert van der; Spierings, Diana C.J.; Bruyn, Marco de; Vugt, Marcel A.T.M. van; Foijer, Floris

doi:10.1038/s41586-022-04847-2

Cited by 193 publications

(125 citation statements)

References 57 publications

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“…As is recognized before, IL-6 directly targets the JAK/STAT3 signals and activates the expression of STAT3-targeted genes [ 44 ], which process is reported to highly depends on the cGAS–STING pathway [ 45 ], that we observed an activated state in isolated astrocytes from susceptible mice of depression model from our results. We, therefore, speculated that regulatory roles of β-arrestin2 in IL-6-induced astrocytic dysfunctions may be involved in JAK/STAT3 signaling pathways.…”

Section: Resultssupporting

confidence: 80%

β-Arrestin2-biased Drd2 agonist UNC9995 alleviates astrocyte inflammatory injury via interaction between β-arrestin2 and STAT3 in mouse model of depression

Yang

Song

Yao

et al. 2022

J Neuroinflammation

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Background Major depressive disorder (MDD) is a prevalent and devastating psychiatric illness. Unfortunately, the current therapeutic practice, generally depending on the serotonergic system for drug treatment is unsatisfactory and shows intractable side effects. Multiple evidence suggests that dopamine (DA) and dopaminergic signals associated with neuroinflammation are highly involved in the pathophysiology of depression as well as in the mechanism of antidepressant drugs, which is still in the early stage of study and well worthy of investigation. Methods We established two chronic stress models, including chronic unpredictable mild stress (CUMS), and chronic social defeat stress (CSDS), to complementarily recapitulate depression-like behaviors. Then, hippocampal tissues were used to detect inflammation-related molecules and signaling pathways. Pathological changes in depressive mouse hippocampal astrocytes were examined by RNA sequencing. After confirming the dopamine receptor 2 (Drd2)/β-arrestin2 signaling changes in the depressive mice brain, we then established the depressive mouse model using the β-arrestin2 knockout mice or administrating the β-arrestin2-biased Drd2 agonist to investigate the roles. Label-free mass spectrometry was used to identify the β-arrestin2-binding proteins as the underlying mechanisms. We modeled neuroinflammation with interleukin-6 (IL-6) and corticosterone treatment and characterized astrocytes using multiple methods including cell viability assay, flow cytometry, and confocal immunofluorescence. Results Drd2-biased β-arrestin2 pathway is significantly changed in the progression of depression, and genetic deletion of β-arrestin2 aggravates neuroinflammation and depressive-like phenotypes. Mechanistically, astrocytic β-arrestin2 retains STAT3 in the cytoplasm by structural combination with STAT3, therefore, inhibiting the JAK–STAT3 pathway-mediated inflammatory activation. Furtherly, pharmacological activation of Drd2/β-arrestin2 pathway by UNC9995 abolishes the inflammation-induced loss of astrocytes and ameliorates depressive-like behaviors in mouse model for depression. Conclusions Drd2/β-arrestin2 pathway is a potential therapeutic target for depression and β-arrestin2-biased Drd2 agonist UNC9995 is identified as a potential anti-depressant strategy for preventing astrocytic dysfunctions and relieving neuropathological manifestations in mouse model for depression, which provides insights for the therapy of depression.

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Section: Resultssupporting

confidence: 80%

β-Arrestin2-biased Drd2 agonist UNC9995 alleviates astrocyte inflammatory injury via interaction between β-arrestin2 and STAT3 in mouse model of depression

Yang

Song

Yao

et al. 2022

J Neuroinflammation

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“…A very recent study showed that STING signaling inactivation impaired the survival of triple negative breast cancer cells. The chromosomal instability in these cells leads to DNA release by micronuclei into the cytoplasm promoting STING activation and cancer progression [ 40 ]. In this context, our data suggest that the combination dl922-947 /PDS might promote an anti-tumor role by inactivating STING signaling independently on G4 structures.…”

Section: Discussionmentioning

confidence: 99%

Combination of dl922-947 Oncolytic Adenovirus and G-Quadruplex Binders Uncovers Improved Antitumor Activity in Breast Cancer

Napolitano

Somma

Castellano

et al. 2022

Cells

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G-quadruplexes (G4s) are nucleic secondary structures characterized by G-tetrads. G4 motif stabilization induces DNA damage and cancer cell death; therefore, G4-targeting small molecules are the focus of clinical investigation. DNA destabilization induced by G4 ligands might potentiate the anticancer activity of agents targeting DNA or inhibiting its repair such as oncolytic viruses. This study represents the first approach combining G4 ligands, BRACO-19 (B19), pyridostatin (PDS), and the adenovirus dl922-947 in breast cancer cells. We demonstrated that G4 binders and dl922-947 induce cytotoxicity in breast cancer cells (MDA-MB-231 and MCF-7) and at higher doses in other neoplastic cell lines of thyroid (BHT-101 cells) and prostate (PC3 cells). G4 binders induce G4 motifs distributed in the S and G2/M phases in MCF-7 cells. G4 binder/dl922-947 combination increases cell cytotoxicity and the accumulation in subG0/G1. Indeed, G4 binders favor viral entry and replication with no effect on coxsackie and adenovirus receptor. Notably, dl922-947 induces G4 motifs and its combination with PDS potentiates this effect in MCF-7 cells. The agents alone or in combination similarly enhanced cell senescence. Additionally, PDS/dl922-947 combination inactivates STING signaling in MDA-MB-231 cells. Our results suggest that G4 binder/virotherapy combination may represent a novel therapeutic anticancer approach.

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“…Recent reports indicate that STING activity in early tumors can prevent tumor initiation [179] while at later stages, chronic STING activation is essential for tumor cell survival [180] and is a poor prognostic marker for cancer patients [179,181]. To fully appreciate the role of STING in tumorigenesis, investigation of the crosstalk between STING expression and inflammatory activity and metabolic rewiring is essential.…”

Section: Discussionmentioning

confidence: 99%