TY - JOUR
T1 - Inhibition of mitochondrial respiration by the anticancer agent 2-methoxyestradiol
AU - Hagen, Thilo
AU - D'Amico, Gabriela
AU - Quintero, Marisol
AU - Palacios-Callender, Miriam
AU - Hollis, Veronica
AU - Lam, Francis
AU - Moncada, Salvador
N1 - Hagen, Thilo D'Amico, Gabriela Quintero, Marisol Palacios-Callender, Miriam Hollis, Veronica Lam, Francis Moncada, Salvador Biochem Biophys Res Commun. 2004 Sep 24;322(3):923-9.
PY - 2004/9/24
Y1 - 2004/9/24
N2 - 2-Methoxyestradiol (2ME2), a naturally occurring metabolite of estradiol, is known to have antiproliferative, antiangiogenic, and proapoptotic activity. Mechanistically, 2ME2 has been shown to downregulate hypoxia-inducible factor 1α (HIF1α) and to induce apoptosis in tumour cells by generating reactive oxygen species (ROS). In this study we report that 2ME2 inhibits mitochondrial respiration in both intact cells and submitochondrial particles, and that this effect is due to inhibition of complex I of the mitochondrial electron transport chain (ETC). The prevention by 2ME2 of hypoxia-induced stabilisation of HIF1α in HEK293 cells was found not to be due to an effect on HIF1α synthesis but rather to an effect on protein degradation. This is in agreement with our recent observation using other inhibitors of mitochondrial respiration which bring about rapid degradation of HIF1α in hypoxia due to increased availability of oxygen and reactivation of prolyl hydroxylases. The concentrations of 2ME2 that inhibited complex I also induced the generation of ROS. 2ME2 did not, however, cause generation of ROS in 143B rho - cells, which lack a functional mitochondrial ETC. We conclude that inhibition of mitochondrial respiration explains, at least in part, the effect of 2ME2 on hypoxia-dependent HIF1α stabilisation and cellular ROS production. Since these actions of 2ME2 occur at higher concentrations than those known to inhibit cell proliferation, it remains to be established whether they contribute to its therapeutic effect. © 2004 Elsevier Inc. All rights reserved.
AB - 2-Methoxyestradiol (2ME2), a naturally occurring metabolite of estradiol, is known to have antiproliferative, antiangiogenic, and proapoptotic activity. Mechanistically, 2ME2 has been shown to downregulate hypoxia-inducible factor 1α (HIF1α) and to induce apoptosis in tumour cells by generating reactive oxygen species (ROS). In this study we report that 2ME2 inhibits mitochondrial respiration in both intact cells and submitochondrial particles, and that this effect is due to inhibition of complex I of the mitochondrial electron transport chain (ETC). The prevention by 2ME2 of hypoxia-induced stabilisation of HIF1α in HEK293 cells was found not to be due to an effect on HIF1α synthesis but rather to an effect on protein degradation. This is in agreement with our recent observation using other inhibitors of mitochondrial respiration which bring about rapid degradation of HIF1α in hypoxia due to increased availability of oxygen and reactivation of prolyl hydroxylases. The concentrations of 2ME2 that inhibited complex I also induced the generation of ROS. 2ME2 did not, however, cause generation of ROS in 143B rho - cells, which lack a functional mitochondrial ETC. We conclude that inhibition of mitochondrial respiration explains, at least in part, the effect of 2ME2 on hypoxia-dependent HIF1α stabilisation and cellular ROS production. Since these actions of 2ME2 occur at higher concentrations than those known to inhibit cell proliferation, it remains to be established whether they contribute to its therapeutic effect. © 2004 Elsevier Inc. All rights reserved.
KW - 2-Methoxyestradiol
KW - Apoptosis
KW - Hypoxia-inducible factor
KW - Mitochondria
KW - Reactive oxygen species
U2 - 10.1016/j.bbrc.2004.07.204
DO - 10.1016/j.bbrc.2004.07.204
M3 - Article
SN - 1090-2104
VL - 322
SP - 923
EP - 929
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 3
ER -