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S1P signaling regulates adaptation to hypoxia


We established that the SphK1/S1P signaling regulates the transcription factor hypoxia inducible HIF-1α and HIF-2α in diverse cancer cell lineages (glioblastoma, prostate, breast, lung, renal cell carcinoma).

In vivo studies established that inhibiting S1P signaling inhibits intratumoral hypoxia and sensitize to standard chemotherapy in prostate cancer and renal cell carcinoma animal models, by increasing intratumoral blood perfusion (vascular normalization).

Overall these findings demonstrate that SphK1/S1P signaling may act as a canonical regulator of HIF-1α and HIF-2α expression in hypoxic tumors, giving support to its inhibition as a therapeutic strategy that could contribute to reduce HIF-1 and/or HIF-2 activity in cancer.


Cuvillier vignette 1.jpgRepresentative images of immunofluorescence double staining for endothelial cells (CD34) and pericytes (αSMA) in paraffin sections obtained from tumors of animals treated with 50 mg/kg anti-S1P mAb or IgG control, showing a vascular remodeling with improved pericyte coverage.Red, CD34 staining; green, αSMA staining. Counterstaining was done with DAPI .