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2,3,5-tris(Glutathion-S-yl)hydroquinone (TGHQ)-mediated apoptosis of human promyelocytic leukemia cells is preceded by mitochondrial cytochrome c release in the absence of a decrease in the mitochondrial membrane potential.
Toxicol Sci. 2005 Jul; 86(1):92-100.TS

Abstract

2,3,5-tris(Glutathion-S-yl)hydroquinone (TGHQ), a metabolite of benzene, induces apoptosis in human promyelocytic leukemia (HL-60) cells. However, the mechanisms by which TGHQ induces apoptosis are unclear, and they were the focus of the present investigation. TGHQ stimulated the rapid formation (30 min) of reactive oxygen species (ROS) in HL-60 cells, and co-treatment with catalase or the antioxidant N-acetylcysteine (NAC) completely blocked TGHQ-induced apoptosis, implicating a causative role for ROS in HL-60 cell death. Western blot analysis revealed the complete disappearance of pro-caspase 9 between 1 and 2 hours after exposure of HL-60 cells to TGHQ, concomitant with the appearance of cleaved caspase 9 and increases in caspase 9 activity. The appearance of two cleaved forms of caspase 3 occurred subsequent to increases in caspase 9 activity. Levels of the anti-apoptotic Bcl-2 protein remained constant during TGHQ-induced apoptosis of HL-60 cells, but Bcl-2 S70 phosphorylation decreased. In contrast, changes in the subcellular localization of the pro-apoptotic molecule Bax were observed, with a rapid (15-60 min) increase in the ratio of cytosolic to mitochondrial Bax. Cytochrome c release from mitochondria to the cytosol occurred after Bax translocation and the dephosphorylation of pS70 Bcl-2. However the mitochondrial inner transmembrane potential (deltapsi(m)) was maintained, even after cytochrome c was released from the mitochondria. Cyclosporin A, an inhibitor of the mitochondrial membrane permeability transition pore (PTP), did not completely rescue HL-60 cells from apoptosis. Taken together, we conclude that TGHQ facilitates ROS production, alters the post-translational modification of Bcl-2 and subcellular localization of Bax, culminating in the release of cytochrome c and caspase activation.

Authors+Show Affiliations

Yang MY
Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas at Austin, Austin, Texas 78712, USA.
Lau SS
No affiliation info available
Monks TJ
No affiliation info available

MeSH

ApoptosisCaspase 9CaspasesCytochromes cGlutathioneHL-60 CellsHumansHydroquinonesLeukemia, Promyelocytic, AcuteMembrane PotentialsMitochondriaReactive Oxygen SpeciesSubcellular FractionsTumor Cells, Cultured

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15800030

Citation

Yang, Mi Young, et al. "2,3,5-tris(Glutathion-S-yl)hydroquinone (TGHQ)-mediated Apoptosis of Human Promyelocytic Leukemia Cells Is Preceded By Mitochondrial Cytochrome C Release in the Absence of a Decrease in the Mitochondrial Membrane Potential." Toxicological Sciences : an Official Journal of the Society of Toxicology, vol. 86, no. 1, 2005, pp. 92-100.
Yang MY, Lau SS, Monks TJ. 2,3,5-tris(Glutathion-S-yl)hydroquinone (TGHQ)-mediated apoptosis of human promyelocytic leukemia cells is preceded by mitochondrial cytochrome c release in the absence of a decrease in the mitochondrial membrane potential. Toxicol Sci. 2005;86(1):92-100.
Yang, M. Y., Lau, S. S., & Monks, T. J. (2005). 2,3,5-tris(Glutathion-S-yl)hydroquinone (TGHQ)-mediated apoptosis of human promyelocytic leukemia cells is preceded by mitochondrial cytochrome c release in the absence of a decrease in the mitochondrial membrane potential. Toxicological Sciences : an Official Journal of the Society of Toxicology, 86(1), 92-100.
Yang MY, Lau SS, Monks TJ. 2,3,5-tris(Glutathion-S-yl)hydroquinone (TGHQ)-mediated Apoptosis of Human Promyelocytic Leukemia Cells Is Preceded By Mitochondrial Cytochrome C Release in the Absence of a Decrease in the Mitochondrial Membrane Potential. Toxicol Sci. 2005;86(1):92-100. PubMed PMID: 15800030.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 2,3,5-tris(Glutathion-S-yl)hydroquinone (TGHQ)-mediated apoptosis of human promyelocytic leukemia cells is preceded by mitochondrial cytochrome c release in the absence of a decrease in the mitochondrial membrane potential. AU - Yang,Mi Young, AU - Lau,Serrine S, AU - Monks,Terrence J, Y1 - 2005/03/30/ PY - 2005/4/1/pubmed PY - 2005/10/12/medline PY - 2005/4/1/entrez SP - 92 EP - 100 JF - Toxicological sciences : an official journal of the Society of Toxicology JO - Toxicol Sci VL - 86 IS - 1 N2 - 2,3,5-tris(Glutathion-S-yl)hydroquinone (TGHQ), a metabolite of benzene, induces apoptosis in human promyelocytic leukemia (HL-60) cells. However, the mechanisms by which TGHQ induces apoptosis are unclear, and they were the focus of the present investigation. TGHQ stimulated the rapid formation (30 min) of reactive oxygen species (ROS) in HL-60 cells, and co-treatment with catalase or the antioxidant N-acetylcysteine (NAC) completely blocked TGHQ-induced apoptosis, implicating a causative role for ROS in HL-60 cell death. Western blot analysis revealed the complete disappearance of pro-caspase 9 between 1 and 2 hours after exposure of HL-60 cells to TGHQ, concomitant with the appearance of cleaved caspase 9 and increases in caspase 9 activity. The appearance of two cleaved forms of caspase 3 occurred subsequent to increases in caspase 9 activity. Levels of the anti-apoptotic Bcl-2 protein remained constant during TGHQ-induced apoptosis of HL-60 cells, but Bcl-2 S70 phosphorylation decreased. In contrast, changes in the subcellular localization of the pro-apoptotic molecule Bax were observed, with a rapid (15-60 min) increase in the ratio of cytosolic to mitochondrial Bax. Cytochrome c release from mitochondria to the cytosol occurred after Bax translocation and the dephosphorylation of pS70 Bcl-2. However the mitochondrial inner transmembrane potential (deltapsi(m)) was maintained, even after cytochrome c was released from the mitochondria. Cyclosporin A, an inhibitor of the mitochondrial membrane permeability transition pore (PTP), did not completely rescue HL-60 cells from apoptosis. Taken together, we conclude that TGHQ facilitates ROS production, alters the post-translational modification of Bcl-2 and subcellular localization of Bax, culminating in the release of cytochrome c and caspase activation. SN - 1096-6080 UR - https://www.unboundmedicine.com/medline/citation/15800030/235_tris_Glutathion_S_yl_hydroquinone__TGHQ__mediated_apoptosis_of_human_promyelocytic_leukemia_cells_is_preceded_by_mitochondrial_cytochrome_c_release_in_the_absence_of_a_decrease_in_the_mitochondrial_membrane_potential_ DB - PRIME DP - Unbound Medicine ER -