Targeting HIF2? translation with Tempol in VHL-deficient clear cell renal cell carcinoma.

ABSTRACT: The tumor suppressor gene, Von Hippel-Lindau (VHL), is frequently mutated in the most common form of kidney cancer, clear cell renal cell carcinoma (CCRCC). In hypoxic conditions, or when there is a VHL mutation, the hypoxia inducible factors, HIF1? and HIF2?, are stabilized and transcribe a panel of genes associated with cancer such as vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor (PDGF), and glucose transporter 1 (GLUT1). Recent studies in clear cell kidney cancer have suggested that HIF2?, but not HIF1?, is the critical oncoprotein in the VHL pathway. Therefore, targeting HIF2? could provide a potential therapeutic approach for patients with advanced CCRCC. Since iron regulatory protein 1 (IRP1) is known to inhibit the translation of HIF2?, we investigated whether Tempol, a stable nitroxide that activates IRP1 towards IRE-binding, might have a therapeutic effect on a panel of human CCRCC cells expressing both HIF1? and HIF2?. We first evaluated the protein expression of HIF1? and HIF2? in 15 different clear cell renal carcinoma cell lines established from patient tumors in our laboratory. Tempol decreased the expression of HIF2?, and its downstream targets in all the cell lines of the panel. This effect was attributed to a dramatic increase of IRE-binding activity of IRP1. Several cell lines were found to have an increased IRP1 basal activity at 20% O2 compared to 5% O2, which may lower HIF2? expression in some of the cell lines in a VHL-independent manner. Taken together our data identify Tempol as an agent with potential therapeutic activity targeting expression of HIF2? in VHL-deficient clear cell kidney cancer and illustrate the importance of studying biochemical processes at relevant physiological O2 levels.

SUBMITTER: Sourbier C 

PROVIDER: S-EPMC3717806 | biostudies-other | 2012 Nov

REPOSITORIES: biostudies-other