Published online before print September 4, 2008

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(American Journal of Pathology. 2008;173:1186-1201.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.071183

Hypoxia Inducible Factor-1 Inactivation Unveils a Link between Tumor Cell Metabolism and Hypoxia-Induced Cell Death

Elena Favaro^*, Giorgia Nardo^*, Luca Persano^*, Massimo Masiero^*, Lidia Moserle^*, Rita Zamarchi, Elisabetta Rossi^*, Giovanni Esposito, Mario Plebani, Ulrike Sattler, Thomas Mann, Wolfgang Mueller-Klieser, Vincenzo Ciminale^*, Alberto Amadori^* and Stefano Indraccolo

From the Department of Oncology and Surgical Sciences,^* Oncology Section, University of Padova, Padova, Italy; Istituto Oncologico Veneto-Instituto di Ricovero e Cura Scientifico, Padova, Italy; Department of Laboratory Medicine, Medical and Surgical Sciences, University of Padova, Padova, Italy; and Institute of Physiology and Pathophysiology, University of Mainz, Mainz, Germany

Hypoxia and the acquisition of a glycolytic phenotype are intrinsic features of the tumor microenvironment. The hypoxia inducible factor-1 (HIF-1) pathway is activated under hypoxic conditions and orchestrates a complex transcriptional program that enhances cell survival. Although the consequences of HIF-1 inactivation in cancer cells have been widely investigated, only a few studies have addressed the role of HIF-1 in the survival of cancer cells endowed with different glycolytic capacities. In this study, we investigated this aspect in ovarian cancer cells. Hypoxia-induced toxicity was increased in highly glycolytic cells compared with poorly glycolytic cells; it was also associated with a sharp decrease in intracellular ATP levels and was prevented by glucose supplementation. Stable HIF-1 silencing enhanced hypoxia-induced cell death in vitro due to a lack of cell cycle arrest. Tumors bearing attenuated HIF-1 levels had similar growth rates and vascularization as did controls, but tumors showed higher proliferation levels and increased necrosis. Moreover, tumors formed by HIF-1 deficient cells had higher levels of lactate and lower ATP concentrations than controls as shown by metabolic imaging. The findings that such metabolic properties can affect the survival of cancer cells under hypoxic conditions and that these properties contribute to the determination of the consequences of HIF-1 inactivation could have important implications on the understanding of the effects of anti-angiogenic and HIF-1-targeting drugs in cancer.