夏普
芳香烃受体
犬尿氨酸
细胞凋亡
下调和上调
吲哚胺2,3-双加氧酶
半胱氨酸蛋白酶
犬尿氨酸途径
化学
凋亡抑制因子
癌症研究
分子生物学
细胞生物学
生物
色氨酸
生物化学
程序性细胞死亡
氨基酸
基因
转录因子
作者
Anna Leja-Szpak,Marta Góralska,Paweł Link-Lenczowski,Urszula Czech,Katarzyna Nawrot-Porąbka,Joanna Bonior,Jolanta Jaworek
出处
期刊:Anti-cancer Agents in Medicinal Chemistry
[Bentham Science]
日期:2020-01-24
卷期号:19 (17): 2079-2090
被引量:11
标识
DOI:10.2174/1871520619666190415165212
摘要
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 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.
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