A therapeutic role for targeting c-Myc/Hif-1-dependent signaling pathways

Klaus Podar, Kenneth C Anderson

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

75 Citations (Scopus)

Abstract

Deregulated c-Myc occurs in ∼30% of human cancers. Similarly, hypoxiainducible factor (HIF) is commonly overexpressed in a variety of human malignancies. Under physiologic conditions, HIF inhibits c-Myc activity; however, when deregulated oncogenic c-Myc collaborates with HIF in inducing the expression of VEGF, PDK1 and hexokinase 2. Most of the knowledge of HIF derives from studies investigating a role of HIF under hypoxic conditions, however, HIF-1α stabilization is also found in normoxic conditions. Specifically, under hypoxic conditions HIF-1-mediated regulation of oncogenic c-Myc plays a pivotal role in conferring metabolic advantages to tumor cells as well as adaptation to the tumorigenic micromilieu. In addition, our own results show that under normoxic conditions oncogenic c-Myc is required for constitutive high HIF-1 protein levels and activity in Multiple Myeloma (MM) cells, thereby influencing VEGF secretion and angiogenic activity within the bone marrow microenvironment. Further studies are needed to delineate the functional relevance of HIF, MYC, and the HIF-MYC collaboration in MM and other malignancies, also integrating the tumor microenvironment and the cellular context. Importantly, early studies already demonstrate promising preclinical of novel agents, predominantly small molecules, which target c-Myc, HIF or both.

Original languageEnglish
Pages (from-to)1722-1728
Number of pages7
JournalCell Cycle
Volume9
Issue number9
DOIs
Publication statusPublished - 01 May 2010
Externally publishedYes

Keywords

  • Hexokinase/metabolism
  • Humans
  • Hypoxia-Inducible Factor 1/metabolism
  • Multiple Myeloma/genetics
  • Protein Serine-Threonine Kinases/metabolism
  • Proto-Oncogene Proteins c-myc/antagonists & inhibitors
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Signal Transduction
  • Vascular Endothelial Growth Factor A/metabolism
  • HIF
  • Tumor microenvironment
  • c-Myc
  • Targeted therapy

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology
  • Developmental Biology

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