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Pharmacological Targeting of STING-Dependent IL-6 Production in Cancer Cells
Sumaiah S Al-Asmari1,2, Aleksandra Rajapakse3, Tomalika R Ullah1,2
1Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.
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.
Insights
Genotoxic DNA damage activates STING signaling in cancer cells, often causing rapid production of pro-tumorigenic IL-6 independently of interferon responses. This highlights STING
Area of Science:
- Immunology and Cancer Biology: Investigating the dual role of STING pathway activation in cancer cell response to genotoxic stress.
Background:
- STING (STimulator of INterferon Genes) pathway activation by genotoxic stress can induce anti-tumoral interferon-beta (IFN-β) production.
- The STING pathway's association with pro-tumorigenic gene expression, like IL-6, is poorly understood, particularly concerning chronic vs. acute signaling during genotoxic treatment.
Purpose of the Study:
- To investigate the rapid induction of pro-tumorigenic IL-6 by genotoxic DNA damage in STING-expressing cancer cells.
- To delineate the roles of canonical and non-canonical STING signaling in IL-6 production and assess the impact of STING inhibition on cancer cell growth.
Main Methods:
- Analysis of STING-expressing cancer cells from the NCI60 panel for IL-6 expression following genotoxic DNA damage.
- Assessment of STING signaling dependency (canonical vs. non-canonical) and downstream effectors (ERK1/2) in response to camptothecin (CPT).
- Evaluation of pharmacological STING inhibition and ERK1/2 inhibition on IL-6 production and cancer cell colony formation (MG-63 cells).
Main Results:
- Approximately 50% of STING-expressing cancer cells showed rapid IL-6 induction upon genotoxic damage, often independent of type-I IFN responses.
- Genotoxic damage induced IL-6 via both canonical and non-canonical STING signaling in a subset of cells; canonical STING inhibition did not broadly block IL-6, but ERK1/2 inhibition did.
- Prolonged canonical STING inhibition increased colony formation in MG-63 cells, indicating a growth-restraining role of STING in certain contexts.
Conclusions:
- Genotoxic DNA damage frequently triggers rapid, pro-tumorigenic IL-6 production in cancer cells via canonical and non-canonical STING activation, independent of IFN signatures.
- The findings reveal the complex, often acute pro-tumorigenic role of STING in human cancers under genotoxic stress.
- Inhibition of ERK1/2 may be a strategy to mitigate DNA-damage-induced pro-tumorigenic IL-6, while preserving the anti-proliferative STING-interferon axis benefits.
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