The Opposite Effect of L-kynurenine and Ahr Inhibitor Ch223191 on Apoptotic Protein Expression in Pancreatic Carcinoma Cells (Panc-1)

Author(s):

Anna Leja-Szpak*, Marta Góralska, Paweł Link-Lenczowski, Urszula Czech, Katarzyna Nawrot-Porąbka, Joanna Bonior and Jolanta Jaworek   Pages 2079 - 2090 ( 12 )

Abstract:

<P>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). </P><P> 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-&#954;B signaling. </P><P> 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. </P><P> 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-&#954;B 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. </P><P> 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-&#954;B 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.</P>

Keywords:

L-kynurenine, L-tryptophan, IDO, AhR, pancreatic human carcinoma cells - PANC-1, apoptosis, caspases expression.

Affiliation:

Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow

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