The IGFR1 inhibitor NVP-AEW541 disrupts a pro-survival and pro-angiogenic IGF-STAT3-HIF1 pathway in human glioblastoma cells

Biochem Pharmacol. 2010 Aug 15;80(4):455-62. doi: 10.1016/j.bcp.2010.05.011. Epub 2010 May 19.

Abstract

Inappropriate activation of the IGF (insulin-like growth factor) system has been implicated in the growth and progression of a number of tumor types. Recent evidence indicates a possible role for the IGF system in modulating/mediating tumor cell response to hypoxia, a common occurrence in solid tumors, and particularly in malignant gliomas, causing tumor cells either to die, or to mount a pleiotropic adaptive response that is mainly orchestrated through activation of the hypoxia-inducible transcription factor HIF1. Experimental evidence suggests possible links between IGF- and HIF1-dependent signaling pathways, as well as a role for activated STAT3 in mediating their activities. Interestingly, igf2 is among the target genes transactivated by HIF1, thereby providing the missing link in a hypothetical autocrine self-amplifying circuit. The present study investigates the presence of the IGF-HIF1-VEGF axis in the human glioma cell line U-87 MG, and characterizes its molecular effectors. Our results show that exogenous IGF-I causes IGF1R and STAT3 activation, and increases HIF1alpha protein levels and HIF1 trascriptional activity, inducing VEGF release; a similar response, mediated by IGF-II release, is observed following HIF1alpha stabilization. The existence of an autocrine loop is confirmed by its down-regulation following inactivation of IGF1R (using the IGF1R-specific tyrosine kinase inhibitor NVP-AEW541), STAT3 (transfecting the cells with an expression vector encoding a dominant negative form of STAT3), or HIF1 (using the small molecule inhibitor YC-1). The ability of NVP-AEW541 to block this circuit could be beneficial in suppressing the growth and angiogenic potential of hypoxic glial tumors.

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Synergism
  • Glioblastoma / pathology*
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Insulin-Like Growth Factor I / metabolism*
  • Pyrimidines / pharmacology*
  • Pyrroles / pharmacology*
  • Receptor, IGF Type 1 / antagonists & inhibitors*
  • STAT3 Transcription Factor / metabolism*

Substances

  • Angiogenesis Inhibitors
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • NVP-AEW541
  • Pyrimidines
  • Pyrroles
  • STAT3 Transcription Factor
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1