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Anticancer Agents Med Chem. 2019 Apr 15. doi: 10.2174/1871520619666190415165212. [Epub ahead of print]

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

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1
Department of Medical Physiology, Faculty of Health Sciences, Jagiellonian Medical College, Krakow. Poland.

Abstract

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.

METHOD:

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 of anti-apoptotic cIAP-1, cIAP-2, XIAP and Bcl-2 expression and a decrease of 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 IDO-dependent 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.

KEYWORDS:

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

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