Targeting DNA damage response pathways to activate the STING innate immune signaling pathway in human cancer cells

FEBS Journal ◽  
2021 ◽  
Author(s):  
Joanne Wayne ◽  
Teresa Brooks ◽  
Alexandra Landras ◽  
Andrew J. Massey
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Dna Damage Response ◽  
Human Cancer ◽  
Innate Immune ◽  
Human Cancer Cells ◽  
Innate Immune Signaling ◽  
Immune Signaling Pathway ◽  
Damage Response ◽  
Innate Immune Signaling Pathway

scholarly journals An assay to measure poly(ADP ribose) glycohydrolase (PARG) activity in cells

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 736 ◽  
Author(s):  
Dominic I. James ◽  
Stephen Durant ◽  
Kay Eckersley ◽  
Emma Fairweather ◽  
Louise A. Griffiths ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Human Cancer ◽  
Immunofluorescence Assay ◽  
Methylmethane Sulfonate ◽  
Human Cancer Cells ◽  
Small Molecule Inhibition ◽  
Damage Response ◽  
Well Assay ◽  
In Cells

After a DNA damage signal multiple polymers of ADP ribose attached to poly(ADP) ribose (PAR) polymerases (PARPs) are broken down by the enzyme poly(ADP) ribose glycohydrolase (PARG). Inhibition of PARG leads to a failure of DNA repair and small molecule inhibition of PARG has been a goal for many years. To determine whether biochemical inhibitors of PARG are active in cells we have designed an immunofluorescence assay to detect nuclear PAR after DNA damage. This 384-well assay is suitable for medium throughput high-content screening and can detect cell-permeable inhibitors of PARG from nM to µM potency. In addition, the assay has been shown to work in murine cells and in a variety of human cancer cells. Furthermore, the assay is suitable for detecting the DNA damage response induced by treatment with temozolomide and methylmethane sulfonate (MMS). Lastly, the assay has been shown to be robust over a period of several years.

scholarly journals An assay to measure poly(ADP ribose) glycohydrolase (PARG) activity in cells

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 736 ◽  
Author(s):  
Dominic I. James ◽  
Stephen Durant ◽  
Kay Eckersley ◽  
Emma Fairweather ◽  
Louise A. Griffiths ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Human Cancer ◽  
Immunofluorescence Assay ◽  
Methylmethane Sulfonate ◽  
Human Cancer Cells ◽  
Small Molecule Inhibition ◽  
Damage Response ◽  
Well Assay ◽  
In Cells

After a DNA damage signal multiple polymers of ADP ribose attached to poly(ADP) ribose (PAR) polymerases (PARPs) are broken down by the enzyme poly(ADP) ribose glycohydrolase (PARG). Inhibition of PARG leads to a failure of DNA repair and small molecule inhibition of PARG has been a goal for many years. To determine whether biochemical inhibitors of PARG are active in cells we have designed an immunofluorescence assay to detect nuclear PAR after DNA damage. This 384-well assay is suitable for medium throughput high-content screening and can detect cell-permeable inhibitors of PARG from nM to µM potency. In addition, the assay has been shown to work in murine cells and in a variety of human cancer cells. Furthermore, the assay is suitable for detecting the DNA damage response induced by treatment with temozolomide and methylmethane sulfonate (MMS). Lastly, the assay has been shown to be robust over a period of several years.

scholarly journals Withanolide D Enhances Radiosensitivity of Human Cancer Cells by Inhibiting DNA Damage Non-homologous End Joining Repair Pathway

2020 ◽  
Vol 9 ◽  
Author(s):  
Jerome Lacombe ◽  
Titouan Cretignier ◽  
Laetitia Meli ◽  
E. M. Kithsiri Wijeratne ◽  
Jean-Luc Veuthey ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Human Cancer ◽  
Repair Pathway ◽  
End Joining ◽  
Human Cancer Cells ◽  
Non Homologous End Joining

scholarly journals Secretoglobin 3A2 eliminates human cancer cells through pyroptosis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Shigetoshi Yokoyama ◽  
Shun Nakayama ◽  
Lei Xu ◽  
Aprile L. Pilon ◽  
Shioko Kimura
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Human Cancer ◽  
Cancer Cell Lines ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Lung Cancer Cell ◽  
Small Cell Lung ◽  
Human Cancer Cells

AbstractNon-canonical inflammasome activation that recognizes intracellular lipopolysaccharide (LPS) causes pyroptosis, the inflammatory death of innate immune cells. The role of pyroptosis in innate immune cells is to rapidly eliminate pathogen-infected cells and limit the replication niche in the host body. Whether this rapid cell elimination process of pyroptosis plays a role in elimination of cancer cells is largely unknown. Our earlier study demonstrated that a multi-functional secreted protein, secretoglobin (SCGB) 3A2, chaperones LPS to cytosol, and activates caspase-11 and the non-canonical inflammasome pathway, leading to pyroptosis. Here we show that SCGB3A2 exhibits marked anti-cancer activity against 5 out of 11 of human non-small cell lung cancer cell lines in mouse xenographs, while no effect was observed in 6 of 6 small cell lung cancer cell lines examined. All SCGB3A2-LPS-sensitive cells express syndecan 1 (SDC1), a SCGB3A2 cell surface receptor, and caspase-4 (CASP4), a critical component of the non-canonical inflammasome pathway. Two epithelial-derived colon cancer cell lines expressing SDC1 and CASP4 were also susceptible to SCGB3A2-LPS treatment. TCGA analysis revealed that lung adenocarcinoma patients with higher SCGB3A2 mRNA levels exhibited better survival. These data suggest that SCGB3A2 uses the machinery of pyroptosis for the elimination of human cancer cells via the non-canonical inflammasome pathway, and that SCGB3A2 may serve as a novel therapeutic to treat cancer, perhaps in combination with immuno and/or targeted therapies.

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