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The Opposite Effect of L-kynurenine and Ahr Inhibitor Ch223191 on Apoptotic Protein Expression in Pancreatic
Anna Leja-Szpak1, Marta Góralska1, Paweł Link-Lenczowski1
1Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Poland.
Background:
L-kynurenine, derivate of L-tryptophan, is synthetized by indoleamine 2,3-dioxygenase (IDO). The effects of L-kynurenine depend on its binding to an aryl hydrocarbon receptor (AhR).
Objective:
The aim of this study was to investigate the changes within the apoptotic pathway in PANC-1 cells subjected to L-kynurenine or L-tryptophan considering the production of anti-apoptotic proteins from the IAPs and Bcl-2 family, as well as the regulation of NF-κB signaling.
Methods:
The investigated substances were added alone or in combination with the AhR inhibitor (CH223191) to cultures of PANC-1 cells. Cytoplasmic and nuclear proteins were analyzed by immunoblotting and cells were incubated with the investigated substances to determine cytotoxicity and proliferative effects.
Results:
Incubation of PANC-1 cells with L-kynurenine or L-tryptophan resulted in the increase in antiapoptotic cIAP-1, cIAP-2, XIAP and Bcl-2 expression and a decrease in pro-apoptotic Bax. These changes were accompanied by the reduction of active caspases -9, -3 and PARP-1. The treatment leads to translocation and enhanced production of nuclear NF-κB p50 and Bcl-3. Incubation of the cells with AhR blocker either alone or together with L-kynurenine or L-tryptophan resulted in the opposite effect, leading to the downregulation of IAPs and Bcl-2, upregulation of Bax and caspases expression.
Conclusion:
1) L-kynurenine and its precursor promote anti-apoptotic effects through the modulation of IDOdependent pathway and regulation of IAPs, Bcl-2 and NF-κB family members in pancreatic carcinoma cells 2) inhibition of AhR by CH223191 exerts an apoptosis-promoting effect, and this observation might suggest the potential use of this compound in pancreatic cancer therapy.
Insights
L-kynurenine and L-tryptophan exhibit anti-apoptotic effects in pancreatic cancer cells by modulating key signaling pathways. Inhibition of the aryl hydrocarbon receptor (AhR) promotes apoptosis, suggesting therapeutic potential.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- L-kynurenine, a tryptophan derivative synthesized by indoleamine 2,3-dioxygenase (IDO), exerts effects via aryl hydrocarbon receptor (AhR) binding.
- Pancreatic cancer cells (PANC-1) are investigated for their response to L-kynurenine and L-tryptophan.
Purpose of the Study:
- To investigate apoptotic pathway changes in PANC-1 cells treated with L-kynurenine or L-tryptophan.
- To analyze the expression of anti-apoptotic proteins (IAPs, Bcl-2 family) and NF-κB signaling regulation.
- To evaluate the impact of AhR inhibition on these processes.
Main Methods:
- PANC-1 cells were treated with L-kynurenine, L-tryptophan, or an AhR inhibitor (CH223191) alone or in combination.
- Cytoplasmic and nuclear proteins were analyzed using immunoblotting.
- Cytotoxicity and proliferative effects were assessed.
Main Results:
- L-kynurenine and L-tryptophan increased anti-apoptotic proteins (cIAP-1, cIAP-2, XIAP, Bcl-2) and decreased pro-apoptotic Bax.
- Active caspases (-9, -3) and PARP-1 were reduced; nuclear NF-κB p50 and Bcl-3 increased.
- AhR inhibition reversed these effects, promoting apoptosis.
Conclusions:
- L-kynurenine and L-tryptophan exert anti-apoptotic effects in pancreatic cancer cells via IDO-dependent pathways and regulation of IAPs, Bcl-2, and NF-κB.
- AhR inhibition demonstrates apoptosis-promoting effects, indicating potential therapeutic applications in pancreatic cancer.
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