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Blood, 15 March 2007, Vol. 109, No. 6, pp. 2565-2570.
Prepublished online as a Blood First Edition Paper on November 16, 2006; DOI 10.1182/blood-2006-06-032664.
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NEOPLASIA
Hypoxia-inducible transcription factor–1 alpha determines sensitivity of endothelial cells to the proteosome inhibitor bortezomib
Lorenzo Veschini1,
Daniela Belloni1,
Chiara Foglieni2,
Maria Giulia Cangi3,
Marina Ferrarini1,
Federico Caligaris-Cappio1,4, and
Elisabetta Ferrero1
1 Laboratory of Tumor Immunology and Department of Oncology,
2 Department of Cardiology, and
3 Department of Pathology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) H San Raffaele, Milan, Italy;
4 Vita-Salute San Raffaele University School of Medicine, Milan, Italy
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-1 ) is its key mediator. We set up a novel in vitro model of HIF-1 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-1 and nuclear factor kappa B (NF-kB). Significantly, when HUVECs were induced to express HIF-1 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-1 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.
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