Abstract
The sphingosine kinase-1/sphingosine 1-phosphate (SphK1/S1P) signaling pathway has been reported to modulate the expression of the canonical transcription factor hypoxia-inducible HIF-1α in multiple cell lineages. HIF-2α is also frequently overexpressed in solid tumors but its role has been mostly studied in clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, where HIF-2α has been established as a driver of a more aggressive disease. In this study, the role of SphK1/S1P signaling with regard to HIF-2α was investigated in various cancer cell models including ccRCC cells. Under hypoxic conditions or in ccRCC lacking a functional von Hippel-Lindau (VHL) gene and expressing high levels of HIF-2α, SphK1 activity controls HIF-2α expression and transcriptional activity through a phospholipase D (PLD)-driven mechanism. SphK1 silencing promotes a VHL-independent HIF-2α loss of expression and activity and reduces cell proliferation in ccRCC. Importantly, downregulation of SphK1 is associated with impaired Akt and mTOR signaling in ccRCC. Taking advantage of a monoclonal antibody neutralizing extracellular S1P, we show that inhibition of S1P extracellular signaling blocks HIF-2α accumulation in ccRCC cell lines, an effect mimicked when the S1P transporter Spns2 or the S1P receptor 1 (S1P1) is silenced. Here, we report the first evidence that the SphK1/S1P signaling pathway regulates the transcription factor hypoxia-inducible HIF-2α in diverse cancer cell lineages notably ccRCC, where HIF-2α has been established as a driver of a more aggressive disease. These findings demonstrate that SphK1/S1P signaling may act as a canonical regulator of HIF-2α expression in ccRCC, giving support to its inhibition as a therapeutic strategy that could contribute to reduce HIF-2 activity in ccRCC.
Highlights
The bioactive sphingolipid sphingosine 1-phosphate (S1P) is a critical regulator of multifarious physiological and pathophysiological processes including cancer.[1,2,3] S1P can be formed by the phosphorylation of sphingosine, the backbone of sphingolipids, and by the sphingosine kinase-1 (SphK1) isoform.[4]
Hypoxia was hypoxia-inducible factors (HIFs)-2α as a driver of a more aggressive disease has been firmly established.[30,31] associated with a remarkable expression of HIF-2α, which was significantly reduced by siSphK1 treatment (Figures 1b and f), We previously identified SphK1/S1P signaling as a new modulator of HIF-1α activity under hypoxia owing to a decreased proteasome degradation of HIF-1α subunit mediated by the Akt/GSK3β pathway in various cancer cell models.[32]
Because phospholipase D (PLD) activity has been involved in the control of HIF-2α expression in ccRCC35 and is an upstream regulator of SphK1 in a different physiological context,[36] we examined the interactions between PLD and SphK1 signaling with regard to HIF-2α expression
Summary
The bioactive sphingolipid sphingosine 1-phosphate (S1P) is a critical regulator of multifarious physiological and pathophysiological processes including cancer.[1,2,3] S1P can be formed by the phosphorylation of sphingosine, the backbone of sphingolipids, and by the sphingosine kinase-1 (SphK1) isoform.[4].
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