2ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIF

Nicola J. Mabjeesh, Daniel Escuin, Theresa M. LaVallee, Victor S. Pribluda, Glenn M. Swartz, Michelle S. Johnson, Margaret T. Willard, Hua Zhong, Jonathan W. Simons, Paraskevi Giannakakou

Research output: Contribution to journalArticlepeer-review

652 Scopus citations

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-α 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.

Original languageEnglish
Pages (from-to)363-375
Number of pages13
JournalCancer Cell
Volume3
Issue number4
DOIs
StatePublished - 1 Jan 2003
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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