The IGFR1 inhibitor NVP-AEW541 disrupts a pro-survival and pro-angiogenic IGF-STAT3-HIF1 pathway in human glioblastoma cells.
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.
Gariboldi
Marzia B
MB
Department of Structural and Functional Biology, Neuroscience Center, University of Insubria, Varese, Italy. marzia.gariboldi@uninsubria.it
Ravizza
Raffaella
R
Monti
Elena
E
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D050796:STAT3 Transcription Factor / Q000378:metabolism*
D020533:Angiogenesis Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C501177:NVP-AEW541; D011743:Pyrimidines; D011758:Pyrroles; D050796:STAT3 Transcription Factor; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1