Intracellular STING inactivation sensitizes breast cancer cells to genotoxic agents

Gaston, Julie; Cheradame, Laura; Yvonnet, Vanessa; Déas, Olivier; Poupon, Marie‐France; Judde, Jean-Gabriel; Cairo, Stefano; Goffin, Vincent

doi:10.18632/oncotarget.12858

Cited by 59 publications

(62 citation statements)

References 64 publications

(96 reference statements)

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“…For example, in breast cancer, STING and its downstream signaling may suppress the tumor or the cancer metastasis . In contrast, STING is also required for cell survival and regrowth in breast cancer . However, the results of the present study do not clarify whether the HBV‐triggered NF‐κB signaling pathway causes liver diseases and tumor development.…”

Section: Discussioncontrasting

confidence: 65%

High-level expression of STING restricts susceptibility to HBV by mediating type III IFN induction

et al. 2018

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Hepatitis B virus (HBV) is a hepatotropic DNA virus causing hepatic diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. To study HBV, human hepatoma HepG2 cells are currently used as an HBV infectious cell culture model worldwide. HepG2 cells exhibit susceptibility to HBV by exogenously expressing sodium taurocholate cotransporting polypeptide (NTCP). We herein demonstrated that human immortalized hepatocyte NKNT-3 cells exhibited susceptibility to HBV by exogenously expressing NTCP (NKNT-3/NTCP cells). By comparing cyclic GMP-AMP synthetase (cGAS)-stimulator of interferon genes (STING) signaling pathway in several NKNT-3/NTCP cell-derived cell clones, we found that STING was highly expressed in cell clones exhibiting resistance but not susceptibility to HBV. High-level expression of STING was implicated in HBV-triggered induction of type III IFN and a pro-inflammatory cytokine, IL-6. In contrast, RNAi-mediated knockdown of STING inhibited type III IFN induction and restored the levels of HBV total transcript in an HBV-infected cell clone exhibiting resistance to HBV. These results suggest that STING regulates susceptibility to HBV by its expression levels. STING may thus be a novel target for anti-HBV strategies. K E Y W O R D Shepatitis B virus, hepatocellular carcinoma, host innate immune response, STING, type III interferon

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Section: Discussioncontrasting

confidence: 65%

High-level expression of STING restricts susceptibility to HBV by mediating type III IFN induction

et al. 2018

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“…Additionally, STING can also participate on tumour progression. In a model of breast cancer, the activation of IFN-STAT1 signalling by STING enhanced cell survival and increased the resistance to DNA damage induced chemotherapy [242]. These results highlight the importance of context specificity to the use of STING inhibitors for cancer therapy.…”

Section: Implications For Immunotherapymentioning

confidence: 79%

Replication Stress, DNA Damage, Inflammatory Cytokines and Innate Immune Response

Ragu

Matos-Rodrigues

Lopez

2020

Genes

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Complete and accurate DNA replication is essential to genome stability maintenance during cellular division. However, cells are routinely challenged by endogenous as well as exogenous agents that threaten DNA stability. DNA breaks and the activation of the DNA damage response (DDR) arising from endogenous replication stress have been observed at pre-or early stages of oncogenesis and senescence. Proper detection and signalling of DNA damage are essential for the autonomous cellular response in which the DDR regulates cell cycle progression and controls the repair machinery. In addition to this autonomous cellular response, replicative stress changes the cellular microenvironment, activating the innate immune response that enables the organism to protect itself against the proliferation of damaged cells. Thereby, the recent descriptions of the mechanisms of the pro-inflammatory response activation after replication stress, DNA damage and DDR defects constitute important conceptual novelties. Here, we review the links of replication, DNA damage and DDR defects to innate immunity activation by pro-inflammatory paracrine effects, highlighting the implications for human syndromes and immunotherapies.Genes 2020, 11, 409 2 of 26 formed when nascent transcripts re-anneal to their template DNA, displacing the non-template strand as single-stranded DNA (ssDNA) [12]. Elevated R-loop levels cause DNA damage and genome instability. The loss of RNA processing and regulatory factors increases R-loop levels, causing R-loop dependent DNA damage in eukaryotic cells [13][14][15][16].DNA breaks and activation of the DNA damage response (DDR), arising from endogenous replication stress, have been observed at early or precancerous stages, and adaptation to replication stress plays an important role in tumour development [17][18][19][20]. The DDR protects genome stability through the precise coordination of a network of pathways, ensuring faithful transmission of genetic material, including DNA replication, repair and recombination, cell cycle checkpoint and chromosome segregation. Ultimately, these autonomous cell responses induce senescence or cell death [21][22][23][24][25]. All these processes prevent the proliferation of cells bearing DNA damage and/or genetic rearrangements. In agreement, syndromes caused by mutations in DDR and/or DNA repair factors are often associated with high genetic instability, cancer predisposition and premature ageing [24,[26][27][28]. In addition to these cell-autonomous responses, protective process(es) also act at the organism level. Such mechanism(s) involve the modification of the cellular microenvironment and ultimately the activation of innate immunity.The inflammatory response is a universal cell-intrinsic response to infections or tissue damage. Inflammation, which is triggered when innate immune cells detect infection, for example, eliminates the initial cause of cell injury, clears out necrotic cells and tissues damaged from the original insult and from the inflammatory process, and initiates ...

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“…Chemotherapy-induced genotoxic stress drove a type I IFN response across a panel of breast cancer cell lines, and STING pathway silencing abrogated this response. [105] Damage-induced IFN response has also been observed following exposure to other clinically relevant agents, including etoposide, camptothecin, mitomycin C, and adriamycin. [106] Interestingly, STING activation also occurs following Cre-mediated DNA cutting[107], raising the possibility that in vivo gene-editing techniques that generate targeted DNA lesions, such as Cre/loxP, CRISPR/Cas9, and TALEN systems, may be accompanied by activation of the innate immune system and an immune response against the edited cell.…”

Section: Dna Repair Factors Beyond Mutational Load Can Also Impact Anmentioning

confidence: 99%

DNA Damage and Repair Biomarkers of Immunotherapy Response

et al. 2017

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DNA damaging agents are widely used in clinical oncology and exploit deficiencies in tumor DNA repair. Given the expanding role of immune checkpoint blockade as a therapeutic strategy, the interaction of tumor DNA damage with the immune system has recently come into focus, and it is now clear that the tumor DNA repair landscape has an important role in driving response to immune checkpoint blockade. Here, we summarize the mechanisms by which DNA damage and genomic instability have been found to shape the anti-tumor immune response and describe clinical efforts to use DNA repair biomarkers to guide use of immune-directed therapies.

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Intracellular STING inactivation sensitizes breast cancer cells to genotoxic agents

Cited by 59 publications

References 64 publications

High-level expression of STING restricts susceptibility to HBV by mediating type III IFN induction

High-level expression of STING restricts susceptibility to HBV by mediating type III IFN induction

Replication Stress, DNA Damage, Inflammatory Cytokines and Innate Immune Response

DNA Damage and Repair Biomarkers of Immunotherapy Response

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