STING protects breast cancer cells from intrinsic and genotoxic-induced DNA instability via a non-canonical, cell-autonomous pathway

STING (Stimulator of Interferon Genes) is an endoplasmic reticulum-anchored adaptor of the innate immunity best known to trigger pro-inflammatory cytokine expression in response to pathogen infection. In cancer, this canonical pathway can be activated by intrinsic or drug-induced genomic instability...

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Vydáno v:	Oncogene Ročník 40; číslo 49; s. 6627 - 6640
Hlavní autoři:	Cheradame, Laura, Guerrera, Ida Chiara, Gaston, Julie, Schmitt, Alain, Jung, Vincent, Goudin, Nicolas, Pouillard, Marion, Radosevic-Robin, Nina, Modesti, Mauro, Judde, Jean-Gabriel, Cairo, Stefano, Goffin, Vincent
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 09.12.2021 Nature Publishing Group Nature Publishing Group [1987-....]
Témata:	13/51 13/89 14/1 14/28 631/337/1427 631/67/1347 631/80/2373 82/29 82/58 96/109 96/21 Animals Antitumor activity Apoptosis Biomarkers, Tumor - genetics Biomarkers, Tumor - metabolism Breast cancer Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Breast Neoplasms - prevention & control Cancer Cancer cells Cell Biology Cell culture Cell Proliferation Cell survival Chemotherapy Deoxyribonucleic acid Development and progression DNA DNA Damage DNA-dependent protein kinase Endoplasmic reticulum Female Gene Expression Regulation, Neoplastic Genetic aspects Genomic Instability Genotoxicity Health aspects Human Genetics Humans Immune response Immunosurveillance Inflammation Innate immunity Interferon Internal Medicine Life Sciences Medicine Medicine & Public Health Membrane proteins Membrane Proteins - genetics Membrane Proteins - metabolism Mice Microsatellite instability Neoplasm Recurrence, Local - genetics Neoplasm Recurrence, Local - metabolism Neoplasm Recurrence, Local - pathology Neoplasm Recurrence, Local - prevention & control Nucleotidyltransferases - genetics Nucleotidyltransferases - metabolism Oncology Oncology, Experimental Ovarian cancer Prognosis Survival Rate Tumor cell lines Tumor Cells, Cultured Tumors Xenograft Model Antitumor Assays France Cellular imaging Breast cancer DNA damage and repair
ISSN:	0950-9232, 1476-5594, 1476-5594
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Popis
Shrnutí:	STING (Stimulator of Interferon Genes) is an endoplasmic reticulum-anchored adaptor of the innate immunity best known to trigger pro-inflammatory cytokine expression in response to pathogen infection. In cancer, this canonical pathway can be activated by intrinsic or drug-induced genomic instability, potentiating antitumor immune responses. Here we report that STING downregulation decreases cell survival and increases sensitivity to genotoxic treatment in a panel of breast cancer cell lines in a cell-autonomous manner. STING silencing impaired DNA Damage Response (53BP1) foci formation and increased DNA break accumulation. These newly identified properties were found to be independent of STING partner cGAS and of its canonical pro-inflammatory pathway. STING was shown to partially localize at the inner nuclear membrane in a variety of breast cancer cell models and clinical tumor samples. Interactomics analysis of nuclear STING identified several proteins of the DNA Damage Response, including the three proteins of the DNA-PK complex, further supporting a role of STING in the regulation of genomic stability. In breast and ovarian cancer patients that received adjuvant chemotherapy, high STING expression is associated with increased risk of relapse. In summary, this study highlights an alternative, non-canonical tumor-promoting role of STING that opposes its well-documented function in tumor immunosurveillance.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0950-9232 1476-5594 1476-5594
DOI:	10.1038/s41388-021-02037-4