Mechanism underlying cytotoxicity of thialysine, lysine analog, toward human acute leukemia Jurkat T cells

• Published in: Biochemical pharmacology 2003-12, Vol.66 (12), p.2291-2300
• Main Authors: Jun, Do Youn, Rue, Seok Woo, Han, Kyu Hyun, Taub, Dennis, Lee, Young Sup, Bae, Young Seuk, Kim, Young Ho
• Format: Article
• Language: English
• Subjects: Apoptosis; bcl-X Protein; Bcl-xL; Biological and medical sciences; Caspase cascade; Caspases - metabolism; cdks; Cell Cycle - drug effects; Cell Survival - drug effects; Cell-cycle arrest; Cyclins; Cysteine - analogs & derivatives; Cysteine - pharmacology; Cytochromes c - metabolism; Enzyme Activation - drug effects; Humans; Jurkat Cells; Leukemia; Lysine - chemistry; Lysine analog; Medical sciences; Mitochondria - drug effects; Mitochondria - enzymology; Mitochondrial cytochrome c; Pharmacology. Drug treatments; Protein Synthesis Inhibitors - pharmacology; Proto-Oncogene Proteins c-bcl-2 - pharmacology; Thialysine; Tumor Cells, Cultured
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2003.08.030

We first report the mechanism for the inhibitory effect of the lysine analog, thialysine on human acute leukemia Jurkat T cells. When Jurkat T cells were treated with thialysine (0.32–2.5 mM), apoptotic cell death along with several biochemical events such as mitochondrial cytochrome c release, caspase-9 activation, caspase-3 activation, degradation of poly (ADP-ribose) polymerase, and DNA fragmentation was induced in a dose- and time-dependent manner. However, these thialysine-induced apoptotic events were significantly abrogated by an ectopic expression of Bcl-xL, which is known to block mitochondrial cytochrome c release. Decylubiquinone, a mitochondrial permeability transition pore inhibitor, also suppressed thialysine-induced apoptotic events. Comparison of the thialysine-induced alterations in the cell cycle distribution between Jurkat T cells transfected with Bcl-xL gene (J/Bcl-xL) and Jurkat T cells transfected with vector (J/Neo) revealed that the apoptotic cells were mainly derived from the cells accumulated in S and G2/M phases following thialysine treatment. The interruption of cell cycle progression in the presence of thialysine was accompanied by a significant decline in the protein level of cdk4, cdk6, cdc2, cyclin A, cyclin B1, and cyclin E. These results demonstrate that the cytotoxic activity of thialysine toward Jurkat T cells is attributable to not only apoptotic cell death mediated by a mitochondria-dependent death signaling pathway, but also interruption of cell cycle progression by a massive down-regulation in the level of cdks and cyclins.