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

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.

SUBMITTER: Chen MH

PROVIDER: S-EPMC4695139 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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

Chen Ming-Huang MH Yen Chueh-Chuan CC Cheng Chi-Tung CT Wu Ren-Chin RC Huang Shih-Chiang SC Yu Chung-Shan CS Chung Yi-Hsiu YH Liu Chun-Yu CY Chang Peter Mu-Hsin PM Chao Yee Y Chen Ming-Han MH Chen Yu-Fen YF Chiang Kun-Chun KC Yeh Ta-Sen TS Chen Tzu Chi TC Huang Chi-Ying F CY Yeh Chun-Nan CN

Oncotarget 20150901 27

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, wh ...[more]

PMID: 26090720

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

Publications

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

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