Hypoxia-Inducible Factors and Sphingosine 1-Phosphate Signaling

Olivier      Cuvillier; Isabelle      Ader

Abstract

Hypoxia, defined as reduced tissue oxygen concentration, is a characteristic of solid tumors and is an indicator of unfavorable diagnosis in patients. At the cellular level, the adaptation to hypoxia is under the control of two related transcription factors, HIF-1α and HIF-2α (Hypoxia-Inducible Factor), which activate expression of genes promoting angiogenesis, metastasis, increased tumor growth and resistance to treatments. A role for HIF-1α and HIF-2α is also emerging in hematologic malignancies such as lymphoma and l eukemia. Recent studies have identified the sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) signaling pathway - which elicits various cellular processes including cell proliferation, cell survival or angiogenesis - as a new regulator of HIF-1α or HIF-2α activity. This review will consider how targeting the SphK1/S1P signaling could represent an attractive strategy for therapeutic intervention in cancer.

Keywords: Hypoxia, Hypoxia inducible factor, Sphingosine 1-Phosphate, Sphingosine kinase, cancer therapy, PHD, siRNAq, VEGF, GLUT-1, HUVECs, (ROS), PTEN