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PMID: 15782127 Published · ppublish English 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.

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

Oncogene ·Vol. 24 ·No. 23 ·2005-05-26 ·Pages 3797-809

Gao N, Rahmani M, Dent P, Grant S

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.

MeSH Terms
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
Chemicals
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
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Gao Ning
Department of Medicine, Virginia Commonwealth University/Medical College of Virginia, Richmond, VA 23298, USA.
Rahmani Mohamed
Dent Paul
Grant Steven
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Article Info
Journal
Oncogene
Abbr.
Oncogene
ISSN
0950-9232
DOI
10.1038/sj.onc.1208530
Published
2005-05-26
Pages
3797-809
Language
English
Region
England
NLM ID
8711562
PMCID
PMC1679904
Subset
IM
Grants
NCI NIH HHS · R01 CA100866 · United States
NCI NIH HHS · R01 CA063753 · United States
NCI NIH HHS · R01 CA093738 · United States
NCI NIH HHS · CA 63753 · United States
NCI NIH HHS · CA 100866 · United States
NCI NIH HHS · CA 93738 · United States
External Links
PubMed source DOI: 10.1038/sj.onc.1208530 PMC Full Text View journal details
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