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.
Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
Nicola J
NJ
Mabjeesh
Daniel
D
Escuin
Theresa M
TM
LaVallee
Victor S
VS
Pribluda
Glenn M
GM
Swartz
Michelle S
MS
Johnson
Margaret T
MT
Willard
Hua
H
Zhong
Jonathan W
JW
Simons
Paraskevi
P
Giannakakou
D000077584:2-Methoxyestradiol; D000818:Animals; D015152:Blotting, Northern; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D004268:DNA-Binding Proteins / Q000187:drug effects* / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008222:Lymphokines / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D008870:Microtubules / Q000187:drug effects*; D023421:Models, Animal; D009389:Neovascularization, Pathologic; D009687:Nuclear Proteins / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger; D014157:Transcription Factors; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D004958:Estradiol; D000077584:2-Methoxyestradiol