Abstract

Activation of the STING pathway upon genotoxic treatment of cancer cells has been shown to lead to anti-tumoral effects, mediated through the acute production of interferon (IFN)-β. Conversely, the pathway also correlates with the expression of NF-κB-driven pro-tumorigenic genes, but these associations are only poorly defined in the context of genotoxic treatment, and are thought to correlate with a chronic engagement of the pathway. We demonstrate here that half of the STING-expressing cancer cells from the NCI60 panel rapidly increased expression of pro-tumorigenic IL-6 upon genotoxic DNA damage, often independent of type-I IFN responses. While preferentially dependent on canonical STING, we demonstrate that genotoxic DNA damage induced by camptothecin (CPT) also drove IL-6 production through non-canonical STING signaling in selected cancer cells. Consequently, pharmacological inhibition of canonical STING failed to broadly inhibit IL-6 production induced by CPT, although this could be achieved through downstream ERK1/2 inhibition. Finally, prolonged inhibition of canonical STING signaling was associated with increased colony formation of MG-63 cells, highlighting the duality of STING signaling in also restraining the growth of selected cancer cells. Collectively, our findings demonstrate that genotoxic-induced DNA damage frequently leads to the rapid production of pro-tumorigenic IL-6 in cancer cells, independent of an IFN signature, through canonical and non-canonical STING activation; this underlines the complexity of STING engagement in human cancer cells, with frequent acute pro-tumorigenic activities induced by DNA damage. We propose that inhibition of ERK1/2 may help curb such pro-tumorigenic responses to DNA-damage, while preserving the anti-proliferative effects of the STING-interferon axis.

Highlights

  • Upon activation by cytoplasmic DNA, cyclic guanosine monophosphate–adenosine monophosphate synthase synthesizes cGAMP, which binds to the adaptor protein STING (Zhang et al, 2013)

  • Our results collectively support a direct role for STING signaling in the frequent IL-6 production in response to genotoxic treatment of cancer cells, most often independent of a marked IRF3 signature. We demonstrate that both canonical and non-canonical STING signaling can participate in the rapid IL-6 production seen upon DNA damage in different cancer cells, indicating that the pro-tumorigenic activities of the pathway are not limited to its chronic engagement

  • We have recently reported that expression of the simian virus 40 (SV40) large T antigen could lead to potentiation of cGASSTING engagement in cells treated with low-dose production as surrogate markers of the NF-κB and IRF3 branches of STING activation, respectively (Pépin et al, 2017b; Dunphy et al, 2018), we first showed that low-dose CPT significantly induced the production of both cytokines in TC-1 cells (Figure 1A)

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Summary

Introduction

Upon activation by cytoplasmic DNA, cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase (cGAS) synthesizes cGAMP, which binds to the adaptor protein STING (stimulator of interferon [IFN] genes) (Zhang et al, 2013). This results in STING translocation from the ER to the Golgi, where it is palmitoylated to recruit TANK-binding kinase 1 (TBK1) and the inhibitor of nuclear factor kappa-B kinase subunit epsilon (IKKε) In addition to its immune function in the sensing of cytosolic pathogenic DNA, cGAS can initiate immune responses to endogenous nuclear and mitochondrial DNA (Dou et al, 2017; Wu et al, 2019). Since cancer cells have deregulated cell cycle checkpoints they frequently harbor cytoplasmic DNA, which is increased further upon genotoxic damage and radiotherapy exposure, and can lead to cGAS-STING activation (Chen et al, 2017; Dou et al, 2017; Harding et al, 2017; Mackenzie et al, 2017; Bakhoum et al, 2018; Nassour et al, 2019; Carozza et al, 2020); (Marcus et al, 2018; Schadt et al, 2019; Carozza et al, 2020)

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