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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
Screening-based repurposing identifies potassium dehydroandrographolide succinate (KDAS) as a selective suppressor of
Alvaro Valero-Cortijo1,2, Joan Antoni Shoenenberger-Arnaiz2,3, Victor J Yuste4
1Cellular Stress Pharmacology Unit, Research Group in Immunology and Metabolism, Department of Experimental Medicine, University of Lleida, Lleida, Spain.
Abstract:
Under physiological conditions, tumor necrosis factor-α (TNF-α) favors cell survival through cytoprotective checkpoints, including a FIP200-dependent non-canonical autophagy pathway. Disruption of this checkpoint shifts TNF-α signaling toward apoptosis, a process relevant to epithelial injury in inflammatory bowel disease (IBD). Anti-TNF-α biologics are standard IBD therapy but primarily neutralize extracellular TNF-α without reducing epithelial susceptibility to death. Here, we conducted a two-step screen of 2421 clinically approved compounds in TNF-α-challenged FIP200-deficient cells to identify drugs that restore cytoprotection. Potassium dehydroandrographolide succinate (KDAS) emerged as a top candidate and conferred > 85% cytoprotection in FIP200-deficient HCT116 cells by inhibiting TNF-α-induced, caspase-8-dependent apoptosis without affecting necroptosis. Other andrographolides did not confer cytoprotection, highlighting KDAS specificity. KDAS also suppressed TRAIL-induced apoptosis and protected additional human cell lines and primary human colonic epithelial cells. Although KDAS enhanced early NF-κB and ERK signaling, pharmacological inhibition of these pathways did not abrogate cytoprotection, suggesting that they are dispensable for its protective effect. These findings identify KDAS as a candidate cytoprotective compound capable of preserving epithelial cell viability downstream of TNF-α receptor activation and indicate a pharmacological approach to limit epithelial apoptosis in TNF-α-mediated diseases such as IBD.
Insights
Potassium dehydroandrographolide succinate (KDAS) protects epithelial cells from tumor necrosis factor-α (TNF-α)-induced apoptosis by restoring a key survival pathway. This discovery offers a new therapeutic strategy for inflammatory bowel disease (IBD).
Area of Science:
- Cell Biology
- Immunology
- Pharmacology
Background:
- Tumor necrosis factor-α (TNF-α) normally promotes cell survival via FIP200-dependent autophagy.
- Loss of this checkpoint shifts TNF-α signaling towards apoptosis, contributing to epithelial injury in inflammatory bowel disease (IBD).
- Current anti-TNF-α therapies primarily neutralize extracellular TNF-α, failing to protect epithelial cells from death.
Purpose of the Study:
- To identify clinically approved compounds that restore cytoprotection in FIP200-deficient cells challenged with TNF-α.
- To evaluate the efficacy and specificity of identified compounds in preventing TNF-α-induced apoptosis.
Main Methods:
- A two-step drug screen of 2421 clinically approved compounds was performed on TNF-α-challenged FIP200-deficient HCT116 cells.
- Potassium dehydroandrographolide succinate (KDAS) was identified and further tested for its ability to inhibit apoptosis and protect various cell types.
- NF-κB and ERK signaling pathways were pharmacologically inhibited to assess their role in KDAS-mediated cytoprotection.
Main Results:
- Potassium dehydroandrographolide succinate (KDAS) conferred over 85% cytoprotection in FIP200-deficient cells by inhibiting TNF-α-induced, caspase-8-dependent apoptosis.
- KDAS demonstrated specificity, as other andrographolides lacked cytoprotective effects.
- KDAS also protected additional human cell lines and primary colonic epithelial cells from TRAIL-induced apoptosis and preserved viability downstream of TNF-α receptor activation.
Conclusions:
- KDAS is a potent cytoprotective compound that restores epithelial cell survival by inhibiting TNF-α-induced apoptosis, independent of canonical NF-κB and ERK pathways.
- This study identifies a novel pharmacological approach to limit epithelial apoptosis in TNF-α-mediated diseases like IBD.
- KDAS represents a promising therapeutic candidate for managing epithelial injury in inflammatory conditions.
