Back to Search
Start Over
Identification of SPHK1 as a therapeutic target and marker of poor prognosis in cholangiocarcinoma.
- Source :
-
Oncotarget [Oncotarget] 2015 Sep 15; Vol. 6 (27), pp. 23594-608. - Publication Year :
- 2015
-
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.
- Subjects :
- Amino Alcohols pharmacology
Animals
Apoptosis drug effects
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 mortality
Cholangiocarcinoma pathology
Extracellular Signal-Regulated MAP Kinases antagonists & inhibitors
Female
Gene Expression Profiling
Humans
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 metabolism
Sphingosine-1-Phosphate Receptors
Xenograft Model Antitumor Assays
Adaptor Proteins, Signal Transducing antagonists & inhibitors
Adaptor Proteins, Signal Transducing genetics
Bile Duct Neoplasms genetics
Cholangiocarcinoma genetics
Lysophospholipids metabolism
Sphingosine analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 6
- Issue :
- 27
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 26090720
- Full Text :
- https://doi.org/10.18632/oncotarget.4335