Hypoxia-inducible transcription factor-1 alpha determines sensitivity of endothelial cells to the proteosome inhibitor bortezomib

Lorenzo Veschini, Daniela Belloni, Chiara Foglieni, Maria Giulia Cangi, Marina Ferrarini, Federico Caligaris-Cappio, Elisabetta Ferrero

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70 Citations (Scopus)

Abstract

Angiogenesis is a complex, orchestrated process that plays a critical role in several conditions and has special relevance in the progression of cancer. Hypoxia is the major stimulus for angiogenesis, and hypoxia-inducible transcription factor–1 alpha (HIF-1α) is its key mediator. We set up a novel in vitro model of HIF-1α up-regulation by treating human umbilical vein endothelial cells (HUVECs) with the hypoxia-mimicking deferoxamine (DFO) and found that this condition was sufficient to promote angiogenesis, like the well-known HUVEC model cultured under low pO2. The proteasome inhibitor bortezomib, which induces strong apoptosis in cancer cells, abrogated proliferation and angiogenesis of HUVECs when used at a high concentration (100 nM), yet promoted both functions at a low dosage (10 nM). This double-edged effect appeared to be mediated by differential effects exerted by the different concentrations of bortezomib on 2 master regulators of tumor-associated angiogenesis, HIF-1α and nuclear factor kappa B (NF-kB). Significantly, when HUVECs were induced to express HIF-1α prior to bortezomib treatment, proliferative and angiogenic responses were abolished, and a greatly enhanced proapoptotic effect was promoted with both concentrations of the drug. These findings indicate that HIF-1α up-regulation may sensitize endothelial cells to the antiangiogenic and proapoptotic effects of bortezomib and might be exploited to target tumor-associated vessels in the course of antiangiogenic therapies.
Original languageEnglish
Pages (from-to)2565-2570
JournalBlood
Volume109
Issue number6
DOIs
Publication statusPublished - 15 Mar 2007

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