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

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.

• Authors: Marzia B Gariboldi, Raffaella Ravizza, Elena Monti
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 80 Issue 4 Pg. 455-62 (Aug 15 2010) ISSN: 1873-2968 [Electronic] England
• PMID: 20488164 (Publication Type: Journal Article)
• Copyright: 2010 Elsevier Inc. All rights reserved.

Chemical References

• 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

Topics

• 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)