2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF.
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.
Mesh Terms:
Animals, Blotting, Northern, Breast Neoplasms, DNA-Binding Proteins, Endothelial Growth Factors, Estradiol, Gene Expression Regulation, Neoplastic, Humans, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Immunohistochemistry, Intercellular Signaling Peptides and Proteins, Lymphokines, Mice, Microscopy, Confocal, Microtubules, Models, Animal, Neovascularization, Pathologic, Nuclear Proteins, RNA, Messenger, Transcription Factors, Transcription, Genetic, Tumor Cells, Cultured, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors
Animals, Blotting, Northern, Breast Neoplasms, DNA-Binding Proteins, Endothelial Growth Factors, Estradiol, Gene Expression Regulation, Neoplastic, Humans, Hypoxia-Inducible Factor 1, Hypoxia-Inducible Factor 1, alpha Subunit, Immunohistochemistry, Intercellular Signaling Peptides and Proteins, Lymphokines, Mice, Microscopy, Confocal, Microtubules, Models, Animal, Neovascularization, Pathologic, Nuclear Proteins, RNA, Messenger, Transcription Factors, Transcription, Genetic, Tumor Cells, Cultured, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors
Cancer Cell
Date: Apr. 01, 2003
PubMed ID: 12726862
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