This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ader, I. Articles by Cuvillier, O. Search for Related Content PubMed PubMed Citation Articles by Ader, I. Articles by Cuvillier, O.

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]

This article has been cited by other articles:

				R. S. Singleton, C. P. Guise, D. M. Ferry, S. M. Pullen, M. J. Dorie, J. M. Brown, A. V. Patterson, and W. R. Wilson DNA Cross-Links in Human Tumor Cells Exposed to the Prodrug PR-104A: Relationships to Hypoxia, Bioreductive Metabolism, and Cytotoxicity Cancer Res., May 1, 2009; 69(9): 3884 - 3891. [Abstract] [Full Text] [PDF]

				I. Ader, B. Malavaud, and O. Cuvillier When the Sphingosine Kinase 1/Sphingosine 1-Phosphate Pathway Meets Hypoxia Signaling: New Targets for Cancer Therapy Cancer Res., May 1, 2009; 69(9): 3723 - 3726. [Abstract] [Full Text] [PDF]

				S. E. Schnitzer, A. Weigert, J. Zhou, and B. Brune Hypoxia Enhances Sphingosine Kinase 2 Activity and Provokes Sphingosine-1-Phosphate-Mediated Chemoresistance in A549 Lung Cancer Cells Mol. Cancer Res., March 1, 2009; 7(3): 393 - 401. [Abstract] [Full Text] [PDF]