Identification of SPHK1 as a therapeutic target and marker of poor prognosis in cholangiocarcinoma

Oncotarget. 2015 Sep 15;6(27):23594-608. doi: 10.18632/oncotarget.4335.

Abstract

Cholangiocarcinoma (CCA) is characterized by a uniquely aggressive behavior and lack of effective targeted therapies. After analyzing the gene expression profiles of seven paired intrahepatic CCA microarrays, a novel sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) pathway and a novel target gene, SPHK1, were identified. We hypothesized that therapeutic targeting of this pathway can be used to kill intrahepatic cholangiocarcinoma (CCA) cells. High levels of SPHK1 protein expression, which was evaluated by immunohistochemical staining of samples from 96 patients with intrahepatic CCA, correlated with poor overall survival. The SPHK1 inhibitor SK1-I demonstrated potent antiproliferative activity in vitro and in vivo. SK1-I modulated the balance of ceramide-sphinogosine-S1P and induced CCA apoptosis. Furthermore, SK1-I combined with JTE013, an antagonist of the predominant S1P receptor S1PR2, inhibited the AKT and ERK signaling pathways in CCA cells. Our preclinical data suggest SPHK1/S1P pathway targeting may be an effective treatment option for patients with CCA.

Keywords: SK1-I; cholangiocarcinoma; sphingosine kinase 1; sphingosine-1-phosphate; sphingosine-1-phosphate receptor 2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
  • Adaptor Proteins, Signal Transducing / genetics*
  • Amino Alcohols / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Bile Duct Neoplasms / genetics*
  • Bile Duct Neoplasms / mortality
  • Bile Duct Neoplasms / pathology
  • Bile Ducts / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Ceramides / metabolism
  • Cholangiocarcinoma / genetics*
  • Cholangiocarcinoma / mortality
  • Cholangiocarcinoma / pathology
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Female
  • Gene Expression Profiling
  • Humans
  • Lysophospholipids / metabolism*
  • MAP Kinase Signaling System / drug effects
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Middle Aged
  • Prognosis
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors
  • Pyrazoles / pharmacology
  • Pyridines / pharmacology
  • Receptors, Lysosphingolipid / antagonists & inhibitors
  • Sphingosine / analogs & derivatives*
  • Sphingosine / metabolism
  • Sphingosine-1-Phosphate Receptors
  • Xenograft Model Antitumor Assays

Substances

  • Adaptor Proteins, Signal Transducing
  • Amino Alcohols
  • Ceramides
  • JTE 013
  • Lysophospholipids
  • N-methyl-5-(4'-pentylphenyl)-2-aminopent-4-ene-1,3-diol
  • Pyrazoles
  • Pyridines
  • Receptors, Lysosphingolipid
  • S1PR2 protein, human
  • SPHKAP protein, human
  • Sphingosine-1-Phosphate Receptors
  • sphingosine 1-phosphate
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Sphingosine