Projects per year
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.
Original language | English |
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Article number | 709618 |
Number of pages | 11 |
Journal | Frontiers in Cell and Developmental Biology |
Volume | 9 |
DOIs | |
Publication status | Published - 11 Jan 2022 |
Keywords
- cancer
- DNA damage
- ERK1/2
- IL-6
- Non-canonical STING
- STING
- STING inhibitor
Projects
- 3 Finished
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Attenuating severe infections in chronic inflammatory diseases through modulation of transforming growth factor-B activity
Bardin, P. (Primary Chief Investigator (PCI)), Gantier, M. (Chief Investigator (CI)), Elias, J. (Chief Investigator (CI)) & Loveland, K. (Chief Investigator (CI))
NHMRC - National Health and Medical Research Council (Australia)
1/01/17 → 31/12/21
Project: Research
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Defining a role for TLR7/8 in Helicobacter pylori infection
Gantier, M. (Primary Chief Investigator (PCI)) & Ferrero, R. (Chief Investigator (CI))
NHMRC - National Health and Medical Research Council (Australia)
1/01/15 → 31/12/18
Project: Research
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Uncovering microRNA decay regulation in mammalian cells
Gantier, M. (Primary Chief Investigator (PCI))
ARC - Australian Research Council
23/07/14 → 22/07/18
Project: Research