Essential role for SphK1/S1P signaling to regulate hypoxia-inducible factor 2α expression and activity in cancer
| Autor: | Cécile Gstalder, Yvan Martineau, Bernard Malavaud, Olivier Cuvillier, Leyre Brizuela, David Müller, Isabelle Ader, Stéphane Pyronnet, R A Sabbadini, Pierre Bouquerel, J Laurent |
|---|---|
| Přispěvatelé: | Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Lpath, Lpath Inc |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Sphingosine [CHIM.ORGA]Chemical Sciences/Organic chemistry Cell growth Biology Cell cycle [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biomolecules [q-bio.BM] Cell biology 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Growth factor receptor chemistry 030220 oncology & carcinogenesis Cancer cell Original Article Signal transduction Molecular Biology Protein kinase B Transcription factor |
| Zdroj: | Oncogenesis Oncogenesis, Nature Publishing Group: Open Access Journals-Option C, 2016, 5, pp.e209. ⟨10.1038/oncsis.2016.13⟩ |
| ISSN: | 2157-9024 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|