Biotechnology and Bioprocess Engineering 2022; 27(2): 183-192  
Tacrolimus Induces Apoptosis in Leukemia Jurkat Cells through Inactivation of the Reactive Oxygen Species-dependent Phosphoinositide-3-Kinase/Akt Signaling Pathway
Yung Hyun Choi
Yung Hyun Choi*
Anti-Aging Research Center, Dong-eui University, Busan 47340, Korea Department of Biochemistry, College of Korean Medicine, Dong-eui University, Busan 47227, Korea
Tel: +82-51-890-3319; Fax: +82-51-890-3333
E-mail: choiyh@deu.ac.kr
Received: July 22, 2021; Revised: October 5, 2021; Accepted: October 7, 2021; Published online: April 30, 2022.
© The Korean Society for Biotechnology and Bioengineering. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Tacrolimus, also named FK506, widely used as an immunosuppressant, is a kind of macrolide produced by Streptomyces tsukubaensis. Although tacrolimus is known to induce apoptosis in leukemia cells, its anti-cancer mechanism is still not yet well understood. In this study, we investigated the anti-cancer effect and related mechanisms of tacrolimus in T-cell leukemia Jurkat cells. According to our data, tacrolimus treatment significantly reduced cell viability of Jurkat cells associated with apoptosis induction. Tacrolimus induced the cytosolic release of cytochrome c by destroying mitochondrial integrity, following decrease in the ratio of Bcl-2/Bax expression and truncation of Bid. Tacrolimus also activated caspases and induced cleavage of poly (ADP-ribose) polymerase. However, tacrolimus-mediated growth inhibition was markedly attenuated in the presence of a pan-caspase inhibitor, but not by a specific necroptosis inhibitor, indicating that tacrolimus induced apoptosis but not necrotic cell death in Jurkat cells. In addition, tacrolimus inactivated the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway, and the apoptosis-inducing effect of tacrolimus was further increased in the presence of a PI3K inhibitor. Moreover, tacrolimus increased the production of reactive oxygen species (ROS), whereas the ROS inhibitor, N-acetyl cysteine, significantly attenuated the growth inhibition and inactivation of the PI3K/Akt signaling caused by tacrolimus. These findings suggest that tacrolimus exhibited anti-cancer activity in Jurkat cells by inducing caspase-dependent apoptosis and ROS-dependent inactivation of the PI3K/Akt signaling pathway.
Keywords: tacrolimus, Jurkat cells, apoptosis, reactive oxygen species, phosphoinositide 3-kinase /Akt


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