Targeting angiogenesis via a c-Myc/hypoxia-inducible factor-1α- dependent pathway in multiple myeloma

Jing Zhang, Martin Sattler, Giovanni Tonon, Clemens Grabher, Samir Lababidi, Alexander Zimmerhackl, Marc S. Raab, Sonia Vallet, Yiming Zhou, Marie Astrid Cartron, Teru Hideshima, Yu Tzu Tai, Dharminder Chauhan, Kenneth C. Anderson, Klaus Podar*

*Corresponding author for this work

Research output: Journal article (peer-reviewed)Journal article

84 Citations (Scopus)

Abstract

Bone marrow angiogenesis is associated with multiple myeloma (MM) progression. Here, we report high constitutive hypoxia-inducible factor-1α (Hif-1α) expression in MM cells, which is associated with oncogenic c-Myc. Adrug screen for anti-MM agents that decrease Hif-1α and c-Myc levels identified a variety of compounds, including bortezomib, lenalidomide, enzastaurin, and adaphostin. Functionally, based on transient knockdowns and overexpression, our data delineate a c-Myc/Hif-1α-dependent pathway mediating vascular endothelial growth factor production and secretion. The antiangiogenic activity of our tool compound, adaphostin, was subsequently shown in a zebrafish model and translated into a preclinical in vitro and in vivo model of MM in the bone marrow milieu. Our data, therefore, identify Hif-1α as a novel molecular target in MM and add another facet to anti-MM drug activity.

Original languageEnglish
Pages (from-to)5082-5090
Number of pages9
JournalCancer Research
Volume69
Issue number12
DOIs
Publication statusPublished - 15 Jun 2009
Externally publishedYes

Keywords

  • Adamantane/analogs & derivatives
  • Angiogenesis Inhibitors/pharmacology
  • Animals
  • Blotting, Western
  • Cell Line, Tumor
  • Down-Regulation
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Hydroquinones/pharmacology
  • Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
  • Immunohistochemistry
  • Mice
  • Mice, Nude
  • Multiple Myeloma/blood supply
  • Neovascularization, Pathologic/prevention & control
  • Proto-Oncogene Proteins c-myc/metabolism
  • Vascular Endothelial Growth Factor A/biosynthesis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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