Endocrine Abstracts (2006) 11 P247

IGF-I modulates HIF-1α and HIF-2 α in Kaposi Sarcoma

SB Catrina1, IR Botusan2, A Rantanen1, AI Catrina1, P Pyakurel1, M Axelson1, P Biberfeld1, L Poellinger1 & K Brismar1

1Karolinska Institute, Stockholm, Sweden; 2Karolinska Institute and UMF Carol Davila, Stockholm, Sweden.

Neoangiogenesis is essential for tumor development. Hypoxia inducible factor (HIF), a transcriptional factor composed of two subunits (α and β) plays a key role in this process, activating proangiogenic factors, such as VEGF. The HIF α subunits are critically regulated by oxygen but also modulated by growth factors. Kaposi Sarcoma (KS) is a highly vascular tumor which releases large amounts of VEGF and for which we have recently described an essential role for Insulin-like Growth Factor (IGF) system. We therefore investigated the expression of HIF αs subunits in biopsies from KS tumors and their modulation by IGF-I in KSIMM, a KS cell line.

Both HIF-1α and HIF-2α are expressed in KS biopsies in all tumoral stages. HIF-1α immunopositivity increases through the tumor development with highest expression in late nodular stages.

In KSIMM cells, IGF-I induces accumulation of both HIF α subunits (western blot). The induction suggests a translation mechanism as demonstrated by cycloheximide (CHX) chase experiment coupled with constant RNA levels as evaluated by qRT-PCR. IGF-I induced HIF αs accumulation is followed by increase of HIF function as documented by reporter gene assay and by induction of endogenous target genes as evaluated by qRT-PCR (VEGF-A and GLUT-1) and ELISA (VEGF-A). Blocking the IGF-IR with picropodophyllin (PPP), a specific IGF-IR tyrosine kinase inhibitor, diminishes the basal and IGF-I-dependent induction of both HIF α congeners and VEGF.

These novel findings shed lights on the coupling between the IGF system and HIF pathway in KS and suggest their contribution in the tumor characteristically vascular phenotype.

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