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Sphingosine Kinase 1: A New Modulator of Hypoxia Inducible Factor 1 during Hypoxia in Human Cancer Cells

¹ Centre National de la Recherche Scientifique, Sphingolipids and Cancer Research Laboratory, Institut de Pharmacologie et de Biologie Structurale, UMR5089; ² Université Toulouse III Paul Sabatier; and ³ CHU Toulouse, Hôpital Rangueil, Service d'Urologie et de Transplantation Rénale, Toulouse, France

Requests for reprints: Olivier Cuvillier, Centre National de la Recherche Scientifique, UMR 5089, 31077 Toulouse, France. Phone: 33-5-61-17-55-13; Fax: 33-5-61-17-58-71; E-mail: olivier.cuvillier{at}ipbs.fr.

Key Words: hypoxia • ROS • pVHL • Akt • Sphingosine kinase 1

Here, we provide the first evidence that sphingosine kinase 1 (SphK1), an oncogenic lipid kinase balancing the intracellular level of key signaling sphingolipids, modulates the transcription factor hypoxia inducible factor 1 (HIF-1), master regulator of hypoxia. SphK1 activity is stimulated under low oxygen conditions and regulated by reactive oxygen species. The SphK1-dependent stabilization of HIF-1 levels is mediated by the Akt/glycogen synthase kinase-3β signaling pathway that prevents its von Hippel-Lindau protein–mediated degradation by the proteasome. The pharmacologic and RNA silencing inhibition of SphK1 activity prevents the accumulation of HIF-1 and its transcriptional activity in several human cancer cell lineages (prostate, brain, breast, kidney, and lung), suggesting a canonical pathway. Therefore, we propose that SphK1 can act as a master regulator for hypoxia, giving support to its inhibition as a valid strategy to control tumor hypoxia and its molecular consequences. [Cancer Res 2008;68(20):8635–42]

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