title: Hypoxia inducible factor-1alpha inactivation unveils a link between tumor cell metabolism and hypoxia-induced cell death.
abstract: Hypoxia and the acquisition of a glycolytic phenotype are intrinsic features of the tumor microenvironment. The hypoxia inducible factor-1alpha (HIF-1alpha) pathway is activated under hypoxic conditions and orchestrates a complex transcriptional program that enhances cell survival. Although the consequences of HIF-1alpha inactivation in cancer cells have been widely investigated, only a few studies have addressed the role of HIF-1alpha 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-1alpha silencing enhanced hypoxia-induced cell death in vitro due to a lack of cell cycle arrest. Tumors bearing attenuated HIF-1alpha levels had similar growth rates and vascularization as did controls, but tumors showed higher proliferation levels and increased necrosis. Moreover, tumors formed by HIF-1alpha 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-1alpha inactivation could have important implications on the understanding of the effects of anti-angiogenic and HIF-1alpha-targeting drugs in cancer.
authors.affiliation: Department of Oncology and Surgical Sciences, Oncology Section, University of Padova, Padova, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Favaro
authors.forename: Giorgia
authors.initials: G
authors.lastname: Nardo
authors.forename: Luca
authors.initials: L
authors.lastname: Persano
authors.forename: Massimo
authors.initials: M
authors.lastname: Masiero
authors.forename: Lidia
authors.initials: L
authors.lastname: Moserle
authors.forename: Rita
authors.initials: R
authors.lastname: Zamarchi
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Rossi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Esposito
authors.forename: Mario
authors.initials: M
authors.lastname: Plebani
authors.forename: Ulrike
authors.initials: U
authors.lastname: Sattler
authors.forename: Thomas
authors.initials: T
authors.lastname: Mann
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mueller-Klieser
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Ciminale
authors.forename: Alberto
authors.initials: A
authors.lastname: Amadori
authors.forename: Stefano
authors.initials: S
authors.lastname: Indraccolo
mesh_terms: D000818:Animals; D016923:Cell Death; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D020868:Gene Silencing; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D016086:Lentivirus; D051379:Mice; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering
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