Caspase activation counteracts interferon signaling after G2 checkpoint abrogation by ATR inhibition in irradiated human cancer cells
Recent studies suggest that inhibition of the ATR kinase can potentiate radiation-induced antitumor immune responses, but the extent and mechanisms of such responses in human cancers remain scarcely understood. We aimed to assess whether the ATR inhibitors VE822 and AZD6738, by abrogating the G2 che...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-10-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.981332/full |
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| author | Adrian Eek Mariampillai Sissel Hauge Inger Øynebråten Gro Elise Rødland Alexandre Corthay Alexandre Corthay Randi G. Syljuåsen |
| author_facet | Adrian Eek Mariampillai Sissel Hauge Inger Øynebråten Gro Elise Rødland Alexandre Corthay Alexandre Corthay Randi G. Syljuåsen |
| author_sort | Adrian Eek Mariampillai |
| collection | DOAJ |
| description | Recent studies suggest that inhibition of the ATR kinase can potentiate radiation-induced antitumor immune responses, but the extent and mechanisms of such responses in human cancers remain scarcely understood. We aimed to assess whether the ATR inhibitors VE822 and AZD6738, by abrogating the G2 checkpoint, increase cGAS-mediated type I IFN response after irradiation in human lung cancer and osteosarcoma cell lines. Supporting that the checkpoint may prevent IFN induction, radiation-induced IFN signaling declined when the G2 checkpoint arrest was prolonged at high radiation doses. G2 checkpoint abrogation after co-treatment with radiation and ATR inhibitors was accompanied by increased radiation-induced IFN signaling in four out of five cell lines tested. Consistent with the hypothesis that the cytosolic DNA sensor cGAS may detect DNA from ruptured micronuclei after G2 checkpoint abrogation, cGAS co-localized with micronuclei, and depletion of cGAS or STING abolished the IFN responses. Contrastingly, one lung cancer cell line showed no increase in IFN signaling despite irradiation and G2 checkpoint abrogation. This cell line showed a higher level of the exonuclease TREX1 than the other cell lines, but TREX1 depletion did not enhance IFN signaling. Rather, addition of a pan-caspase inhibitor restored the IFN response in this cell line and also increased the responses in the other cell lines. These results show that treatment-induced caspase activation can suppress the IFN response after co-treatment with radiation and ATR inhibitors. Caspase activation thus warrants further consideration as a possible predictive marker for lack of IFN signaling. |
| first_indexed | 2024-04-12T17:59:21Z |
| format | Article |
| id | doaj.art-7fea646455fc4b5b8ee5d1fb69887e1b |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-04-12T17:59:21Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-7fea646455fc4b5b8ee5d1fb69887e1b2022-12-22T03:22:12ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-10-011210.3389/fonc.2022.981332981332Caspase activation counteracts interferon signaling after G2 checkpoint abrogation by ATR inhibition in irradiated human cancer cellsAdrian Eek Mariampillai0Sissel Hauge1Inger Øynebråten2Gro Elise Rødland3Alexandre Corthay4Alexandre Corthay5Randi G. Syljuåsen6Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, NorwayDepartment of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, NorwayTumor Immunology Lab, Department of Pathology, Oslo University Hospital, Oslo, NorwayDepartment of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, NorwayTumor Immunology Lab, Department of Pathology, Oslo University Hospital, Oslo, NorwayHybrid Technology Hub – Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, Oslo, NorwayDepartment of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, NorwayRecent studies suggest that inhibition of the ATR kinase can potentiate radiation-induced antitumor immune responses, but the extent and mechanisms of such responses in human cancers remain scarcely understood. We aimed to assess whether the ATR inhibitors VE822 and AZD6738, by abrogating the G2 checkpoint, increase cGAS-mediated type I IFN response after irradiation in human lung cancer and osteosarcoma cell lines. Supporting that the checkpoint may prevent IFN induction, radiation-induced IFN signaling declined when the G2 checkpoint arrest was prolonged at high radiation doses. G2 checkpoint abrogation after co-treatment with radiation and ATR inhibitors was accompanied by increased radiation-induced IFN signaling in four out of five cell lines tested. Consistent with the hypothesis that the cytosolic DNA sensor cGAS may detect DNA from ruptured micronuclei after G2 checkpoint abrogation, cGAS co-localized with micronuclei, and depletion of cGAS or STING abolished the IFN responses. Contrastingly, one lung cancer cell line showed no increase in IFN signaling despite irradiation and G2 checkpoint abrogation. This cell line showed a higher level of the exonuclease TREX1 than the other cell lines, but TREX1 depletion did not enhance IFN signaling. Rather, addition of a pan-caspase inhibitor restored the IFN response in this cell line and also increased the responses in the other cell lines. These results show that treatment-induced caspase activation can suppress the IFN response after co-treatment with radiation and ATR inhibitors. Caspase activation thus warrants further consideration as a possible predictive marker for lack of IFN signaling.https://www.frontiersin.org/articles/10.3389/fonc.2022.981332/fullcell cycle checkpointstype I interferon (IFN) signalingradiation therapy (radiotherapy)micronuclei (MN)ATRcaspase |
| spellingShingle | Adrian Eek Mariampillai Sissel Hauge Inger Øynebråten Gro Elise Rødland Alexandre Corthay Alexandre Corthay Randi G. Syljuåsen Caspase activation counteracts interferon signaling after G2 checkpoint abrogation by ATR inhibition in irradiated human cancer cells Frontiers in Oncology cell cycle checkpoints type I interferon (IFN) signaling radiation therapy (radiotherapy) micronuclei (MN) ATR caspase |
| title | Caspase activation counteracts interferon signaling after G2 checkpoint abrogation by ATR inhibition in irradiated human cancer cells |
| title_full | Caspase activation counteracts interferon signaling after G2 checkpoint abrogation by ATR inhibition in irradiated human cancer cells |
| title_fullStr | Caspase activation counteracts interferon signaling after G2 checkpoint abrogation by ATR inhibition in irradiated human cancer cells |
| title_full_unstemmed | Caspase activation counteracts interferon signaling after G2 checkpoint abrogation by ATR inhibition in irradiated human cancer cells |
| title_short | Caspase activation counteracts interferon signaling after G2 checkpoint abrogation by ATR inhibition in irradiated human cancer cells |
| title_sort | caspase activation counteracts interferon signaling after g2 checkpoint abrogation by atr inhibition in irradiated human cancer cells |
| topic | cell cycle checkpoints type I interferon (IFN) signaling radiation therapy (radiotherapy) micronuclei (MN) ATR caspase |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.981332/full |
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