Abstract
Inhibition of angiogenesis is an important new modality for cancer treatment. 2-methoxyestradiol (2ME2) is a novel antitumor and antiangiogenic agent, currently in clinical trials, whose molecular mechanism of action remains unclear. Herein, we report that 2ME2 inhibits tumor growth and angiogenesis at concentrations that efficiently disrupt tumor microtubules (MTs) in vivo. Mechanistically, we found that 2ME2 downregulates hypoxia-inducible factor-1 (HIF) at the posttranscriptional level and inhibits HIF-1-induced transcriptional activation of VEGF expression. Inhibition of HIF-1 occurs downstream of the 2ME2/tubulin interaction, as disruption of interphase MTs is required for HIF-alpha downregulation. These data establish 2ME2 as a small molecule inhibitor of HIF-1 and provide a mechanistic link between the disruption of the MT cytoskeleton and inhibition of angiogenesis.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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2-Methoxyestradiol
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Animals
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Blotting, Northern
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Breast Neoplasms / blood supply
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Breast Neoplasms / drug therapy
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Breast Neoplasms / pathology
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DNA-Binding Proteins / drug effects*
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DNA-Binding Proteins / metabolism
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Endothelial Growth Factors / genetics
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Endothelial Growth Factors / metabolism
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Estradiol / analogs & derivatives
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Estradiol / pharmacology*
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Gene Expression Regulation, Neoplastic
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Humans
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Immunohistochemistry
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism
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Lymphokines / drug effects
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Lymphokines / genetics
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Lymphokines / metabolism
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Mice
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Microscopy, Confocal
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Microtubules / drug effects*
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Models, Animal
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Neovascularization, Pathologic*
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Nuclear Proteins / drug effects*
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Nuclear Proteins / metabolism
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RNA, Messenger
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Transcription Factors*
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Transcription, Genetic
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Tumor Cells, Cultured
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
Substances
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DNA-Binding Proteins
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Endothelial Growth Factors
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HIF1A protein, human
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Hif1a protein, mouse
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Intercellular Signaling Peptides and Proteins
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Lymphokines
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Nuclear Proteins
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RNA, Messenger
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Transcription Factors
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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Estradiol
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2-Methoxyestradiol