title: A novel role of sphingosine kinase-1 in the invasion and angiogenesis of VHL mutant clear cell renal cell carcinoma.
abstract: Sphingosine kinase 1 (SK1), the enzyme responsible for sphingosine 1-phosphate (S1P) production, is overexpressed in many human solid tumors. However, its role in clear cell renal cell carcinoma (ccRCC) has not been described previously. ccRCC cases are usually associated with mutations in von Hippel-Lindau (VHL) and subsequent normoxic stabilization of hypoxia-inducible factor (HIF). We previously showed that HIF-2α up-regulates SK1 expression during hypoxia in glioma cells. Therefore, we hypothesized that the stabilized HIF in ccRCC cells will be associated with increased SK1 expression. Here, we demonstrate that SK1 is overexpressed in 786-0 renal carcinoma cells lacking functional VHL, with concomitant high S1P levels that appear to be HIF-2α mediated. Moreover, examining the TCGA RNA seq database shows that SK1 expression was ∼2.7-fold higher in solid tumor tissue from ccRCC patients, and this was associated with less survival. Knockdown of SK1 in 786-0 ccRCC cells had no effect on cell proliferation. On the other hand, this knockdown resulted in an ∼3.5-fold decrease in invasion, less phosphorylation of focal adhesion kinase (FAK), and an ∼2-fold decrease in angiogenesis. Moreover, S1P treatment of SK1 knockdown cells resulted in phosphorylation of FAK and invasion, and this was mediated by S1P receptor 2. These results suggest that higher SK1 and S1P levels in VHL-defective ccRCC could induce invasion in an autocrine manner and angiogenesis in a paracrine manner. Accordingly, targeting SK1 could reduce both the invasion and angiogenesis of ccRCC and therefore improve the survival rate of patients.
authors: *Stony Brook Cancer Center and the Department of Medicine, Stony Brook University, Health Sciences Center, Stony Brook, New York, USA; Department of Biochemistry, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt; and Northport Veterans Affairs Medical Center, Northport, New York, USA.
authors: Mohamed F
authors: MF
authors: Salama
authors: *Stony Brook Cancer Center and the Department of Medicine, Stony Brook University, Health Sciences Center, Stony Brook, New York, USA; Department of Biochemistry, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt; and Northport Veterans Affairs Medical Center, Northport, New York, USA.
authors: Brittany
authors: B
authors: Carroll
authors: *Stony Brook Cancer Center and the Department of Medicine, Stony Brook University, Health Sciences Center, Stony Brook, New York, USA; Department of Biochemistry, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt; and Northport Veterans Affairs Medical Center, Northport, New York, USA.
authors: Mohamad
authors: M
authors: Adada
authors: *Stony Brook Cancer Center and the Department of Medicine, Stony Brook University, Health Sciences Center, Stony Brook, New York, USA; Department of Biochemistry, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt; and Northport Veterans Affairs Medical Center, Northport, New York, USA.
authors: Michael
authors: M
authors: Pulkoski-Gross
authors: *Stony Brook Cancer Center and the Department of Medicine, Stony Brook University, Health Sciences Center, Stony Brook, New York, USA; Department of Biochemistry, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt; and Northport Veterans Affairs Medical Center, Northport, New York, USA.
authors: Yusuf A
authors: YA
authors: Hannun
authors: *Stony Brook Cancer Center and the Department of Medicine, Stony Brook University, Health Sciences Center, Stony Brook, New York, USA; Department of Biochemistry, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt; and Northport Veterans Affairs Medical Center, Northport, New York, USA lina.obeid@stonybrookmedicine.edu.
authors: Lina M
authors: LM
authors: Obeid
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D007680:Kidney Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008246:Lysophospholipids / Q000096:biosynthesis; D009154:Mutation; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D000081025:Sphingosine-1-Phosphate Receptors; D015854:Up-Regulation; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D000099157:Sphingosine Kinase; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051417:Focal Adhesion Kinase 1; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000081025:Sphingosine-1-Phosphate Receptors; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099157:Sphingosine Kinase; D000099162:Endothelial PAS Domain-Containing Protein 1; C477522:S1PR2 protein, human; C060506:sphingosine 1-phosphate; C496050:PTK2 protein, human; C497446:VHL protein, human
keywords: HIF-2; S1P receptor; focal adhesion kinase; sphingosine 1-phosphate