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

Abstract

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 1A (HIF-1A), master regulator of hypoxia. SphK1 activity is stimulated under low oxygen conditions and regulated by reactive oxygen species. The SphK1-dependent stabilization of HIF-1A levels is mediated by the Akt/glycogen synthase kinase-3B 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-1A 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]

Hypoxia Enhances Sphingosine Kinase 2 Activity and Provokes Sphingosine-1-Phosphate-Mediated Chemoresistance in A549 Lung Cancer Cells

“…Alternatively, hypoxia stimulates the enzymatic activity of SphKs to increase the S1P concentration. These multiple options of hypoxic regulation may explain expression and/or activation of either SphK1 or SphK2 under various experimental settings, such as long-lasting hypoxic exposure periods (32), using CoCl 2 rather than authentic hypoxia (33) or referring to HIF-independent regulation of SphK activity as seen by Ader et al (34) and our study.…”

“…In endothelial cells, Schwalm et al noticed a rapid and long-lasting activation of SphK1 under hypoxia (2-24 h), which was associated with HIF-1-and HIF-2-dependent signaling (32). More recently, activation of SphK1 under hypoxia was related to reactive oxygen species formation, which in turn facilitated stabilization of HIF-1a (34). In A549 cells, we excluded the HIF system to regulate SphK2, because CoCl 2 , a potent inducer of HIF activity, showed no respective activity.…”

“…In opposite, Schwalm et al suggested that both HIF-1 and HIF-2 act in concert to induce SphK1 protein under hypoxic conditions (32). New evidence suggests that SphK1 activity under hypoxia is mediated by reactive oxygen species (34). Irrespective of differences on mechanistic details, increased expression and activation of SphKs and subsequent formation of S1P has been correlated with enhanced survival (29), and an increased synthesis of S1P has been reported under hypoxic conditions (35).…”

SphingomabTM, un anticorps anti-sphingosine 1-phosphate, comme agent anti-hypoxique dans le cancer

“…Une relation entre la voie de signalisation SphK1/S1P et les mécanismes d'adaptation à l'hypoxie a récemment été mise en évidence dans le cancer. Nos précédents travaux avaient montré que l'activité de la sphingosine kinase SphK1 était augmentée lors de l'hypoxie et cela, dans de nombreux modèles tumoraux humains (sein, rein, prostate, gliome, poumon) [13]. Nous avions éga-lement montré que l'inhibition pharmacologique, par la méthode d'interfé-rence ARN, de la SphK1 entraînait une diminution de son activité jusqu'à 90 % en condition d'hypoxie, résultant en une baisse du taux de HIF-1 et de l'expression de ses gènes cibles [13].…”

“…Nos précédents travaux avaient montré que l'activité de la sphingosine kinase SphK1 était augmentée lors de l'hypoxie et cela, dans de nombreux modèles tumoraux humains (sein, rein, prostate, gliome, poumon) [13]. Nous avions éga-lement montré que l'inhibition pharmacologique, par la méthode d'interfé-rence ARN, de la SphK1 entraînait une diminution de son activité jusqu'à 90 % en condition d'hypoxie, résultant en une baisse du taux de HIF-1 et de l'expression de ses gènes cibles [13]. D'un point de vue mécanistique, l'accumulation de HIF-1 dépendante de la S1P repose sur l'activation de la voie de signalisation Akt (protein kinase B [PKB])/GSK3 (glycogen synthase kinase 3b) connue pour réguler la stabilisation de HIF-1 lors d'une hypoxie [14].…”