2-Methoxyestradiol-induced apoptosis in human leukemia cells proceeds through a reactive oxygen species and Akt-dependent process.

Abstract

The effects of 2-Methoxyestradiol (2ME)-induced apoptosis was examined in human leukemia cells (U937 and Jurkat) in relation to mitochondrial injury, oxidative damage, and perturbations in signaling pathways. 2ME induced apoptosis in these cells in a dose-dependent manner associated with release of mitochondrial proteins (cytochrome c, AIF), generation of reactive oxygen species (ROS), downregulation of Mcl-1 and XIAP, and inactivation (dephosphorylation) of Akt accompanied by activation of JNK. In these cells, enforced activation of Akt by a constitutively active myristolated Akt construct prevented 2ME-mediated mitochondrial injury, XIAP and Mcl-1 downregulation, JNK activation, and apoptosis, but not ROS generation. Conversely, 2ME lethality was potentiated by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. Furthermore, in U937 cells, the hydrogen peroxide scavenger catalase and a superoxide dismutase (SOD) mimetic, TBAP, blocked these events, as well as Akt inactivation. Interruption of the JNK pathway by pharmacologic or genetic (e.g. siRNA) means attenuated 2ME-induced mitochondrial injury, XIAP and Mcl-1 downregulation, and apoptosis. Collectively, these findings suggest a hierarchical model of 2ME-related apoptosis induction in human leukemia cells in which 2ME-induced oxidative injury represents a primary event resulting in Akt inactivation, leading, in turn, to JNK activation, and culminating in XIAP and Mcl-1 downregulation, mitochondrial injury, and apoptosis. They also suggest that in human leukemia cells, the Akt pathway plays a critical role in mediating the response to oxidative stress induced by 2ME.

• Authors: Ning Gao, Mohamed Rahmani, Paul Dent, Steven Grant
• Journal: Oncogene (Oncogene) Vol. 24 Issue 23 Pg. 3797-809 (May 26 2005) ISSN: 0950-9232 [Print] England
• PMID: 15782127 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anthracenes
• Chromones
• Morpholines
• Proteins
• Proto-Oncogene Proteins
• Reactive Oxygen Species
• X-Linked Inhibitor of Apoptosis Protein
• XIAP protein, human
• pyrazolanthrone
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Estradiol
• 2-Methoxyestradiol
• AKT1 protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• JNK Mitogen-Activated Protein Kinases

Topics

• 2-Methoxyestradiol
• Anthracenes (pharmacology)
• Apoptosis (drug effects)
• Chromones (pharmacology)
• Dose-Response Relationship, Drug
• Estradiol (analogs & derivatives, pharmacology)
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Jurkat Cells
• Morpholines (pharmacology)
• Phosphatidylinositol 3-Kinases
• Protein Serine-Threonine Kinases (physiology)
• Proteins (antagonists & inhibitors)
• Proto-Oncogene Proteins (physiology)
• Proto-Oncogene Proteins c-akt
• Reactive Oxygen Species (metabolism)
• U937 Cells
• X-Linked Inhibitor of Apoptosis Protein