SPHK1

Gene Summary

Gene:SPHK1; sphingosine kinase 1
Aliases: SPHK
Location:17q25.1
Summary:The protein encoded by this gene catalyzes the phosphorylation of sphingosine to form sphingosine-1-phosphate (S1P), a lipid mediator with both intra- and extracellular functions. Intracellularly, S1P regulates proliferation and survival, and extracellularly, it is a ligand for cell surface G protein-coupled receptors. This protein, and its product S1P, play a key role in TNF-alpha signaling and the NF-kappa-B activation pathway important in inflammatory, antiapoptotic, and immune processes. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:sphingosine kinase 1
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: SPHK1 (cancer-related)

Vishwakarma S, Agarwal R, Goel SK, et al.
Altered Expression of Sphingosine-1-Phosphate Metabolizing Enzymes in Oral Cancer Correlate With Clinicopathological Attributes.
Cancer Invest. 2017; 35(2):139-141 [PubMed] Related Publications
We have determined the gene expression of sphingosine-1-phosphate (S1P) metabolizing enzymes (SphK1, SphK2, SGPL1, SGPP1, SGPP2, PPAP2A, PPAP2B, and PPAP2C) by quantitative real-time polymerase chain reaction in tumor tissues and adjacent normal tissues of 50 oral squamous cell carcinoma (OSCC) patients. Expression of SphK1 and SGPP1 genes was up-regulated significantly in 70% and 75% OSCC tumors respectively. Importantly, expression of SphK2 and PPAP2B was down-regulated in the tumor tissues of 70% OSCC patients. Expression of SphK2 and PPAP2B negatively correlated with tumor-node-metastasis (TNM) staging and tumor volume respectively. Furthermore, LPP1 is an independent predictor of TNM staging and lymph node ratio.

Zhou Y, Han Y, Zhang Z, et al.
MicroRNA-124 upregulation inhibits proliferation and invasion of osteosarcoma cells by targeting sphingosine kinase 1.
Hum Cell. 2017; 30(1):30-40 [PubMed] Related Publications
Increasing evidence has confirmed that the dysregulation of microRNAs (miRNAs) contributes to the proliferation and invasion of human cancers. Previous studies have shown that the dysregulation of miR-124 is in numerous cancers. However, the roles of miR-124 in human osteosarcoma (OS) have not been well clarified. Therefore, this study was to investigate the biological functions and molecular mechanisms of miR-124 in OS cell lines, discussing whether it could be a therapeutic biomarker of OS in the future. In this study, our results demonstrated that miR-124 was down-regulated in OS cell lines and tissues. Furthermore, the low level of miR-124 was associated with increased expression of Sphingosine kinase 1 (SPHK1) in OS cells and tissues. Up-regulation of miR-124 significantly inhibited cell proliferation, invasion, and MMP-2 and -9 expressions of OS cells. Bioinformatics analysis predicted that the SPHK1 was a potential target of miR-124. Further study by luciferase reporter assay demonstrated that miR-124 could directly target SPHK1. Overexpression of SPHK1 in OS cells transfected with miR-124 mimic partially reversed the inhibitory of miR-124. In conclusion, miR-124 inhibited cell proliferation and invasion in OS cells by downregulation of SPHK1, and that downregulation of SPHK1 was essential for the miR-124-inhibited cell invasion and in OS cells.

Lynch KR, Thorpe SB, Santos WL
Sphingosine kinase inhibitors: a review of patent literature (2006-2015).
Expert Opin Ther Pat. 2016; 26(12):1409-1416 [PubMed] Related Publications
INTRODUCTION: Sphingosine kinase (SphK1 & SphK2) is the sole source of the pleiotropic lipid mediator, sphingosine-1-phosphate (S1P). S1P has been implicated in a variety of diseases such as cancer, Alzheimer's disease, sickle cell disease and fibrosis and thus the biosynthetic route to S1P is a logical target for drug discovery. Areas covered: In this review, the authors consider the SphK inhibitor patent literature from 2006-2016 Q1 with the emphasis on composition of matter utility patents. The Espacenet database was queried with the search term 'sphingosine AND kinase' to identify relevant literature. Expert opinion: Early inhibitor discovery focused on SphK1 with a bias towards oncology indications. Structurally, the reported inhibitors occupy the sphingosine 'J-shaped' binding pocket. The lack of cytotoxicity with improved SphK1 inhibitors raises doubt about the enzyme as an oncology target. SphK2 inhibitors are featured in more recent patent applications. Interestingly, both SphK1 and SphK2 inhibition and gene 'knockout' share opposing effects on circulating S1P levels: SphK1 inhibition/gene ablation decreases, while SphK2 inhibition/gene ablation increases, blood S1P. As understanding of S1P's physiological roles increases and more drug-like SphK inhibitors emerge, inhibiting one or both SphK isotypes could provide unique strategies for treating disease.

Fan Z, Jiang H, Wang Z, Qu J
Atorvastatin partially inhibits the epithelial-mesenchymal transition in A549 cells induced by TGF-β1 by attenuating the upregulation of SphK1.
Oncol Rep. 2016; 36(2):1016-22 [PubMed] Related Publications
Statins are the most effective drugs used in the reduction of intracellular synthesis of cholesterol. Numerous studies have confirmed that statins reduce the risk of multiple types of cancers. Statin use in cancer patients is associated with reduced cancer-related mortality. Epithelial-to-mesenchymal transition (EMT), a complicated process programmed by multiple genes, is an important mechanism of cancer metastasis. We explored the effect and mechanism of atorvastatin on the EMT process in A549 cells by establishing an EMT model in vitro induced by TGF-β1, and evaluated the effects of atorvastatin on the lower signaling pathway of TGF-β1 stimulation. Our results showed that atorvastatin partially inhibited the EMT process, and inhibited cell migration and actin filament remodeling. Transcriptional upregulation of ZEB1 and protein sphingosine kinase 1 (SphK1) induced by TGF-β1 was also suppressed. SphK1 plasmid transient transfection strengthened the EMT process induced by TGF-β1 in the presence of atorvastatin. Our experiments confirmed that atorvastatin can partially inhibit the EMT process of non-small cell lung cancer cells induced by TGF-β1 by attenuating the upregulation of SphK1.

Liu H, Zhang CX, Ma Y, et al.
SphK1 inhibitor SKI II inhibits the proliferation of human hepatoma HepG2 cells via the Wnt5A/β-catenin signaling pathway.
Life Sci. 2016; 151:23-9 [PubMed] Related Publications
AIM: Sphingosine 1-phosphate (S1P) promotes cell growth, proliferation and survival. Sphingosine kinase 1 (SphK1), which converts sphingosine to S1P, is a key promoter in cancer. We previously found that the SphK1 inhibitor II (SKI II), suppresses the cell growth and induces apoptosis in human hepatoma HepG2 cells. However, the precise regulatory mechanism and signaling pathway on SKI II inhibiting tumor growth remains unknown.
MAIN METHODS: The expressions of β-catenin and related molecules of Wnt/β-catenin signal were detected by western blot in HepG2 cells. And the mRNA expression of β-catenin was detected by RT-PCR. The Wnt5A gene was silenced by siRNA. The colony formation was determined by staining with crystal violet. And the cell growth was examined by SRB assay and BrdU assay.
KEY FINDINGS: We found that SKI II decreased the expression of β-catenin and the downstream molecules of β-catenin signal pathway and promotes the β-catenin degradation. In addition, SKI II induced the expression of Wnt5A, and then triggered β-catenin degradation. Furthermore, silencing Wnt5A decreased the anti-tumor effects of SKI II through recovering the expressions of β-catenin and downstream molecules of β-catenin signal pathway.
SIGNIFICANCE: SKI II-induced downregulation of HepG2 cell proliferation was associated with Wnt signaling pathway through Wnt5A-mediated β-catenin degradation. Our study revealed that a novel signal pathway was involved in SKI II-inhibited cell proliferation in human hepatoma cells.

Shida D, Inoue S, Yoshida Y, et al.
Sphingosine kinase 1 is upregulated with lysophosphatidic acid receptor 2 in human colorectal cancer.
World J Gastroenterol. 2016; 22(8):2503-11 [PubMed] Free Access to Full Article Related Publications
AIM: To examine the expression of SphK1, an oncogenic kinase that produces sphingosine 1-phosphate (S1P), and its correlation with the expression of LPAR2, a major lysophosphatidic acid (LPA) receptor overexpressed in various cancers, in human colorectal cancer.
METHODS: Real-time reverse-transcription polymerase chain reaction was used to measure the mRNA expression of SphK1, LPAR2, and the three major S1P receptors in 27 colorectal cancer samples and corresponding normal tissue samples. We also examined the correlation between the expression of SphK1 and LPAR2.
RESULTS: Colorectal cancer tissue in 22 of 27 patients had higher levels of SphK1 mRNA than in normal tissue. In two-thirds of the samples, SphK1 mRNA expression was more than two-fold higher than in normal tissue. Consistent with previous reports, LPAR2 mRNA expression in 20 of 27 colorectal cancer tissue samples was higher compared to normal tissue samples. Expression profiles of all three major S1P receptors, S1PR1, S1PR2, and S1PR3, varied without any trend, with no significant difference in expression between cancer and normal tissues. A highly significant positive correlation was found between SphK1 and LPAR2 expression [Pearson's correlation coefficient (r) = 0.784 and P < 0.01]. The mRNA levels of SphK1 and LPAR2 did not correlate with TNM stage.
CONCLUSION: Our findings suggest that S1P and LPA may play important roles in the development of colorectal cancer via the upregulation of SphK1 and LPAR2, both of which could serve as new therapeutic targets in the treatment of colorectal cancer.

Li J, Song Z, Wang Y, et al.
Overexpression of SphK1 enhances cell proliferation and invasion in triple-negative breast cancer via the PI3K/AKT signaling pathway.
Tumour Biol. 2016; 37(8):10587-93 [PubMed] Related Publications
Sphingosine kinase 1 (SphK1) expression is elevated in various cancers and is associated with shorter survival times for patients. However, the molecular mechanism of SphK1 up-regulation in triple-negative breast cancer (TNBC) remains unclear. In this study, we assayed the expression level of SphK1 in TNBC tissues by qRT-PCR and immunohistochemistry. The level of S1P was quantified by ELISA in the serum of TNBC patients. Our results found that the levels of SphK1 and S1P were significantly increased in TNBC patients compared with normal control. Furthermore, knockdown of SphK1 with siRNA decreased TNBC cell proliferation and inhibited cell migration/invasion. These data suggest that SphK1 has an important role in TNBC and presents an attractive therapeutic target for the treatment for TNBC.

Xu Y, Dong B, Huang J, et al.
Sphingosine kinase 1 is overexpressed and promotes adrenocortical carcinoma progression.
Oncotarget. 2016; 7(3):3233-44 [PubMed] Free Access to Full Article Related Publications
Adrenocortical carcinoma (ACC) is a rare endocrine tumor with a very poor prognosis. Sphingosine kinase 1 (SphK1), an oncogenic kinase, has previously been found to be upregulated in various cancers. However, the role of the SphK1 in ACC has not been investigated. In this study, SphK1 mRNA and protein expression levels as well as clinicopathological significance were evaluated in ACC samples. In vitro siRNA knockdown of SphK1 in two ACC cell lines (H295R and SW13) was used to determine its effect on cellular proliferation and invasion. In addition, we further evaluated the effect of SphK1 antagonist fingolimod (FTY720) in ACC in vitro and in vivo, as a single agent or in combination with mitotane, and attempted to explore its anticarcinogenic mechanisms. Our results show a significant over-expression of SphK1 mRNA and protein expression in the carcinomas compared with adenomas (P < 0.01 for all comparisons). Functionally, knockdown of SphK1 gene expression in ACC cell lines significantly decreased cell proliferation and invasion. FTY720 could result in a decreased cell proliferation and induction of apoptosis, and the combination of mitotane and FTY720 resulted in a greater anti-proliferative effect over single agent treatment in SW13 cells. Furthermore, FTY720 could markedly inhibit tumor growth in ACC xenografts. SphK1 expression is functionally associated to cellular proliferation, apoptosis, invasion and mitotane sensitivity of ACC. Our data suggest that SphK1 might be a potential therapeutic target for the treatment of ACC.

Long J, Xie Y, Yin J, et al.
SphK1 promotes tumor cell migration and invasion in colorectal cancer.
Tumour Biol. 2016; 37(5):6831-6 [PubMed] Related Publications
Colorectal cancer (CRC) is one of the most common cancers worldwide. Sphingosine kinase 1 (SphK1), which phosphorylates sphingosine to sphingosine-1-phosphate (S1P), is overexpressed in various types of cancers and may act as an oncogene in tumorigenesis. However, little is known about the role of SphK1 in CRC patients. We studied the expression of SphK1 in 85 cases of CRC tissues by immunohistochemistry, qRT-PCR, and western blot. We also evaluated the effect of SphK1 on cell proliferation and invasion by MTT and transwell invasion assay. SphK1 is overexpressed in CRC tissues and cell lines, and upregulation of SphK1 correlated significantly with the following parameters: lymph node metastasis, liver metastasis, and advanced TNM stage. SphK1 knockdown results in inhibition of cancer cell proliferation. Inhibition of CRC cell migration and invasion is also evident through reversal of EMT by increases in E-cadherin expression and decreases in vimentin expression. In conclusion, SphK1 is associated with the proliferation and invasiveness of CRC cells and the SphK1 gene may contribute to a novel therapeutic approach against CRC.

Maczis M, Milstien S, Spiegel S
Sphingosine-1-phosphate and estrogen signaling in breast cancer.
Adv Biol Regul. 2016; 60:160-5 [PubMed] Related Publications
Breast cancer remains the most common malignant disease in women. The estrogen receptor-α (ERα) and its ligand 17β-estradiol (E2) play important roles in breast cancer. E2 elicits cellular effects by binding to ERα in the cytosol followed by receptor dimerization and translocation to the nucleus where it regulates gene expression by binding to ERE response elements. However, it has become apparent that E2 also exerts rapid non-genomic effects through membrane-associated receptors. There is emerging evidence that this induces formation of the bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P). S1P in turn has been implicated in many processes important in breast cancer progression. One of the enzymes that produce S1P, sphingosine kinase 1 (SphK1), is upregulated in breast cancer and its expression has been correlated with poor prognosis. This review is focused on the role of the SphK/S1P axis in estrogen signaling and breast cancer progression and will discuss new therapeutic approaches targeting this axis for breast cancer treatment.

Lu Z, Zhang W, Gao S, et al.
MiR-506 suppresses liver cancer angiogenesis through targeting sphingosine kinase 1 (SPHK1) mRNA.
Biochem Biophys Res Commun. 2015 Dec 4-11; 468(1-2):8-13 [PubMed] Related Publications
MicroRNAs acting as oncogenes or tumor suppressor genes play crucial roles in human cancers. Sphingosine kinase 1 (SPHK1) and its metabolite sphingosine 1-phosphate (S1P) contribute to tumor angiogenesis. We have reported that the down-regulation of miR-506 targeting YAP mRNA results in the hepatocarcinogenesis. In the present study, we report a novel function of miR-506, which suppresses tumor angiogenesis through targeting SPHK1 mRNA in liver cancer. Bioinformatics analysis showed that miR-506 might target 3'-untranslated region (3'UTR) of SPHK1 mRNA. Then, we validated that by luciferase reporter gene assays. MiR-506 was able to reduce the expression of SPHK1 at the levels of mRNA and protein using reverse transcription-polymerase chain reaction and Western blot analysis in hepatoma HepG2 cells. Functionally, human umbilical vein endothelial cell (HUVEC) tube formation assays demonstrated that the forced miR-506 expression remarkably inhibited the production of S1P in the supernatant of hepatoma cells. The supernatant resulted in the inhibition of tumor angiogenesis. Interestingly, the supernatant with overexpression of SPHK1 could rescue the inhibition of angiogenesis of liver cancer mediated by miR-506. Anti-miR-506 increased the production of S1P in the supernatant of hepatoma cells, but the supernatant with silencing of SPHK1 abolished anti-miR-506-induced acceleration of tumor angiogenesis. Clinically, we observed that the levels of miR-506 were negatively related to those of SPHK1 mRNA in liver cancer tissues. Thus, we conclude that miR-506 depresses the angiogenesis of liver cancer through targeting 3'UTR of SPHK1 mRNA. Our finding provides new insights into the mechanism of tumor angiogenesis.

Lu Z, Xiao Z, Liu F, et al.
Long non-coding RNA HULC promotes tumor angiogenesis in liver cancer by up-regulating sphingosine kinase 1 (SPHK1).
Oncotarget. 2016; 7(1):241-54 [PubMed] Free Access to Full Article Related Publications
Highly up-regulated in liver cancer (HULC) is a long non-coding RNA (lncRNA). We found that HULC up-regulated sphingosine kinase 1 (SPHK1), which is involved in tumor angiogenesis. Levels of HULC were positively correlated with levels of SPHK1 and its product, sphingosine-1-phosphate (S1P), in patients HCC samples. HULC increased SPHK1 in hepatoma cells. Chicken chorioallantoic membrane (CAM) assays revealed that si-SPHK1 remarkably blocked the HULC-enhanced angiogenesis. Mechanistically, HULC activated the promoter of SPHK1 in hepatoma cells through the transcription factor E2F1. Chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA) further showed that E2F1 was capable of binding to the E2F1 element in the SPHK1 promoter. HULC increased the expression of E2F1 in hepatoma cells and levels of HULC were positively correlated with those of E2F1 in HCC tissues. Intriguingly, HULC sequestered miR-107, which targeted E2F1 mRNA 3'UTR, by complementary base pairing. Functionally, si-SPHK1 remarkably abolished the HULC-enhanced tumor angiogenesis in vitro and in vivo. Taken together, we conclude that HULC promotes tumor angiogenesis in liver cancer through miR-107/E2F1/SPHK1 signaling. Our finding provides new insights into the mechanism of tumor angiogenesis.

Matula K, Collie-Duguid E, Murray G, et al.
Regulation of cellular sphingosine-1-phosphate by sphingosine kinase 1 and sphingosine-1-phopshate lyase determines chemotherapy resistance in gastroesophageal cancer.
BMC Cancer. 2015; 15:762 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Resistance to chemotherapy is common in gastroesophageal cancer. Mechanisms of resistance are incompletely characterised and there are no predictive biomarkers in clinical practice for cytotoxic drugs. We used new cell line models to characterise novel chemotherapy resistance mechanisms and validated them in tumour specimens to identify new targets and biomarkers for gastroesophageal cancer.
METHODS: Cell lines were selected for resistance to oxaliplatin, cisplatin and docetaxel and gene expression examined using Affymetrix Exon 1.0 ST arrays. Leads were validated by qRT-PCR and HPLC of tumour metabolites. Protein expression and pharmacological inhibition of lead target SPHK1 was evaluated in independent cell lines, and by immunohistochemistry in gastroesophageal cancer patients.
RESULTS: Genes with differential expression in drug resistant cell lines compared to the parental cell line they were derived from, were identified for each drug resistant cell line. Biological pathway analysis of these gene lists, identified over-represented pathways, and only 3 pathways - lysosome, sphingolipid metabolism and p53 signalling- were identified as over-represented in these lists for all three cytotoxic drugs investigated. The majority of genes differentially expressed in chemoresistant cell lines from these pathways, were involved in metabolism of glycosphingolipids and sphingolipids in lysosomal compartments suggesting that sphingolipids might be important mediators of cytotoxic drug resistance in gastroeosphageal cancers . On further investigation, we found that drug resistance (IC50) was correlated with increased sphingosine kinase 1(SPHK1) mRNA and also with decreased sphingosine-1-phosphate lysase 1(SGPL1) mRNA. SPHK1 and SGPL1 gene expression were inversely correlated. SPHK1:SGPL1 ratio correlated with increased cellular sphingosine-1-phosphate (S1P), and S1P correlated with drug resistance (IC50). High SPHK1 protein correlated with resistance to cisplatin (IC50) in an independent gastric cancer cell line panel and with survival of patients treated with chemotherapy prior to surgery but not in patients treated with surgery alone. Safingol a SPHK1 inhibitor, was cytotoxic as a single agent and acted synergistically with cisplatin in gastric cancer cell lines.
CONCLUSION: Agents that inhibit SPHK1 or S1P could overcome cytotoxic drug resistance in gastroesophageal cancer. There are several agents in early phase human trials including Safingol that could be combined with chemotherapy or used in patients progressing after chemotherapy.

Kim HS, Yoon G, Ryu JY, et al.
Sphingosine kinase 1 is a reliable prognostic factor and a novel therapeutic target for uterine cervical cancer.
Oncotarget. 2015; 6(29):26746-56 [PubMed] Free Access to Full Article Related Publications
Sphingosine kinase 1 (SPHK1), an oncogenic kinase, has previously been found to be upregulated in various types of human malignancy and to play a crucial role in tumor development and progression. Although SPHK1 has gained increasing prominence as an important enzyme in cancer biology, its potential as a predictive biomarker and a therapeutic target in cervical cancer remains unknown. SPHK1 expression was examined in 287 formalin-fixed, paraffin-embedded cervical cancer tissues using immunohistochemistry, and its clinical implications and prognostic significance were analyzed. Cervical cancer cell lines including HeLa and SiHa were treated with the SPHK inhibitors SKI-II or FTY720, and effects on cell survival, apoptosis, angiogenesis, and invasion were examined. Moreover, the effects of FTY720 on tumor growth were evaluated using a patient-derived xenograft (PDX) model of cervical cancer. Immunohistochemical analysis revealed that expression of SPHK1 was significantly increased in cervical cancer compared with normal tissues. SPHK1 expression was significantly associated with tumor size, invasion depth, FIGO stage, lymph node metastasis, and lymphovascular invasion. Patients with high SPHK1 expression had lower overall survival and recurrence-free survival rates than those with low expression. Treatment with SPHK inhibitors significantly reduced viability and increased apoptosis in cervical cancer cells. Furthermore, FTY720 significantly decreased in vivo tumor weight in the PDX model of cervical cancer. We provide the first convincing evidence that SPHK1 is involved in tumor development and progression of cervical cancer. Our data suggest that SPHK1 might be a potential prognostic marker and therapeutic target for the treatment of cervical cancer.

Zhang D, Xia H, Zhang W, Fang B
The anti-ovarian cancer activity by WYE-132, a mTORC1/2 dual inhibitor.
Tumour Biol. 2016; 37(1):1327-36 [PubMed] Related Publications
Epithelial ovarian cancer is the most common and lethal gynecological cancer in USA and around the world, causing major mortality annually. In the current study, we investigated the potential anti-ovarian cancer activity of WYE-132, a mammalian target of rapamycin (mTOR) complex 1/2 (mTORC1/2) dual inhibitor. Our results showed that WYE-132 potently inhibited proliferation of primary and established human ovarian cancer cells. Meanwhile, WYE-132 induced caspase-dependent apoptosis in ovarian cancer cells. At the molecular level, WYE-132 blocked mTORC1/2 activation and inhibited expression of mTOR-regulated genes (cyclin D1 and hypoxia-inducible factor 1α). Interestingly, introducing a constitutively active AKT (caAKT), which restored mTORC1/2 activation in WYE-132-treated ovarian cancer cells, only mitigated (but not abolished) WYE-132-mediated growth inhibition and apoptosis. Further studies showed that WYE-132 inhibited sphingosine kinase-1 (SphK1) activity, leading to pro-apoptotic ceramide production in ovarian cancer cells. Meanwhile, WYE-132-induced cytotoxicity against ovarian cancer cells was inhibited by sphingosine-1-phosphate (S1P) but was aggravated by SphK1 inhibitor SKI-II or C6 ceramide. In vivo, WYE-132 inhibited ovarian cancer cell growth, and its activity was further enhanced when co-administrated with paclitaxel (Taxol). These results demonstrate that WYE-132 inhibits ovarian cancer cell proliferation through mTOR-dependent and mTOR-independent mechanisms and indicate a potential value of WYE-132 in ovarian cancer treatment.

LeBlanc FR, Liu X, Hengst J, et al.
Sphingosine kinase inhibitors decrease viability and induce cell death in natural killer-large granular lymphocyte leukemia.
Cancer Biol Ther. 2015; 16(12):1830-40 [PubMed] Free Access to Full Article Related Publications
Sphingolipid metabolism has been identified as a potential therapeutic target in cancer. Sphingosine-1-phosphate (S1P) is a potent bioactive sphingolipid metabolite produced by sphingosine kinases-1 and -2 (SPHK1 and SPHK2). Elevated SPHK1 has been found in numerous cancer types and been shown to contribute to survival, chemotherapeutic resistance and malignancy. However, its role in large granular Natural Killer (NK) large granular lymphocyte (LGL) leukemia has not been investigated. Here, we examine SPHK1 as a therapeutic target in LGL leukemia. We found that SPHK1 is overexpressed in peripheral blood mononuclear cells (PBMCs) from LGL leukemia patients which results in elevated S1P in the sera. The use of SPHK1 inhibitors, SKI-II or SKI-178, decreased leukemic NK cell viability and induced caspase-dependent apoptosis. SKI-II and SKI-178 restored the sphingolipid balance by increasing ceramide and decreasing S1P in leukemic NKL cells. SKI-II and SKI-178 also induced apoptosis in primary NK-LGLs from leukemia patients. Mechanistic studies in NK-LGL cell lines demonstrated that SKI-178 and SKI-II induced cell cycle arrest at G2/M. We found that SKI-178 induced phosphorylation of Bcl-2 at Ser70, and that this was dependent on CDK1. We further show that SPHK1 inhibition with SKI-178 leads to decreased JAK-STAT signaling. Our data demonstrate that SPHK1 represents a novel therapeutic target for the treatment of NK-LGL leukemia.

Chen MH, Yen CC, Cheng CT, et al.
Identification of SPHK1 as a therapeutic target and marker of poor prognosis in cholangiocarcinoma.
Oncotarget. 2015; 6(27):23594-608 [PubMed] Free Access to Full Article Related Publications
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.

Lu ZP, Xiao ZL, Yang Z, et al.
Hepatitis B virus X protein promotes human hepatoma cell growth via upregulation of transcription factor AP2α and sphingosine kinase 1.
Acta Pharmacol Sin. 2015; 36(10):1228-36 [PubMed] Free Access to Full Article Related Publications
AIM: Sphingosine kinase 1 (SPHK1) is involved in various cellular functions, including cell growth, migration, apoptosis, cytoskeleton architecture and calcium homoeostasis, etc. As an oncogenic kinase, SPHK1 is associated with the development and progression of cancers. The aim of this study was to investigate whether SPHK1 was involved in hepatocarcinogenesis induced by the hepatitis B virus X protein (HBx).
METHODS: The expression of SPHK1 in hepatocellular carcinoma (HCC) tissue and hepatoma cells were measured using qRT-PCR and Western blot analysis. HBx expression levels in hepatoma cells were modulated by transiently transfected with HBx or psi-HBx plasmids. The SPHK1 promoter activity was measured using luciferase reporter gene assay, and the interaction of the transcription factor AP2α with the SPHK1 promoter was studied with chromatin immunoprecipitation assay. The growth of hepatoma cells was evaluated in vitro using MTT and colony formation assays, and in a tumor xenograft model.
RESULTS: A positive correlation was found between the mRNA levels of SPHK1 and HBx in 38 clinical HCC samples (r=+0.727, P<0.01). Moreover, the expression of SPHK1 was markedly increased in the liver cancer tissue of HBx-transgenic mice. Overexpressing HBx in normal liver cells LO2 and hepatoma cells HepG2 dose-dependently increased the expression of SPHK1, whereas silencing HBx in HBx-expressing hepatoma cells HepG2-X and HepG2.2.15 suppressed SPHK1 expression. Furthermore, overexpressing HBx in HepG2 cells dose-dependently increased the SPHK1 promoter activity, whereas silencing HBx in HepG2-X cells suppressed this activity. In HepG2-X cells, AP2α was found to directly interact with the SPHK1 promoter, and silencing AP2α suppressed the SPHK1 promoter activity and SPHK1 expression. Silencing HBx in HepG2-X cells abolished the HBx-enhanced proliferation and colony formation in vitro, and tumor growth in vivo.
CONCLUSION: HBx upregulates SPHK1 through the transcription factor AP2α, which promotes the growth of human hepatoma cells.

Mizutani N, Omori Y, Tanaka K, et al.
Increased SPHK2 Transcription of Human Colon Cancer Cells in Serum-Depleted Culture: The Involvement of CREB Transcription Factor.
J Cell Biochem. 2015; 116(10):2227-38 [PubMed] Related Publications
Sphingosine kinases (SPHK) are important to determine cells' fate by producing sphingosine 1-phosphate. Reportedly, exogenous SPHK2 overexpression induces cell cycle arrest or cell death. However, the regulatory mechanism of SPHK2 expression has not been fully elucidated. Here, we analyzed this issue using human colon cancer cell lines under various stress conditions. Serum depletion (FCS(-)) but not hypoxia and glucose depletion increased mRNA, protein and enzyme activity of SPHK2 but not SPHK1. In HCT116 cells mostly used, SPHK2 activity was predominant over SPHK1, and serum depletion increased both nuclear and cytoplasmic SPHK2 activity. Based on previous reports analyzing cellular response after serum depletion, the temporal changes of intracellular signaling molecules and candidate transcription factors for SPHK2 were examined using serum-depleted HCT116 cells, and performed transfection experiments with siRNA or cDNA of candidate transcription factors. Results showed that the rapid and transient JNK activation followed by CREB activation was the major regulator of increased SPHK2 transcription in FCS(-) culture. EMSA and ChIP assay confirmed the direct binding of activated CREB to the CREB binding site of 5' SPHK2 promoter region. Colon cancer cells examined continued to grow in FCS(-) culture, although mildly, while hypoxia and glucose depletion suppressed cell proliferation or induced cell death, suggesting the different role of SPHK2 in different stress conditions. Because of the unique relationship observed after serum depletion, we examined effects of siRNA for SPHK2, and found the role of SPHK2 as a growth or survival factor but not a cell proliferation inhibitor in FCS(-) culture.

Cheng L, Chen YZ, Peng Y, et al.
Ceramide production mediates cinobufotalin-induced growth inhibition and apoptosis in cultured hepatocellular carcinoma cells.
Tumour Biol. 2015; 36(8):5763-71 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) is a highly aggressive and lethal neoplasm with poor prognosis. The aim of this study is to investigate the anticancer activity of cinobufotalin, a bufadienolide isolated from toad venom, in cultured HCC cells, and to study the underlying mechanisms. We found that cinobufotalin (at nmol/L) significantly inhibited HCC cell growth and survival while inducing considerable cell apoptosis. Further, cinobufotalin inhibited sphingosine kinase 1 (SphK1) activity and induced pro-apoptotic ceramide production. Ceramide synthase-1 small hairpin RNA (shRNA)-depletion inhibited cinobufotalin-induced ceramide production and HCC cell apoptosis. On the other hand, the glucosylceramide synthase (GCS) inhibitor 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) facilitated cinobufotalin-induced ceramide production and cell apoptosis. SphK1 inhibitor II (SKI-II), similar to cinobufotalin, increased cellular ceramide level and promoted HCC cell apoptosis. Finally, we observed that cinobufotalin inactivated Akt-S6K1 signaling in HepG2 cells, which was again inhibited by ceramide synthase-1 shRNA-depletion. In conclusion, the results of this study suggest that cinobufotalin induces growth inhibition and apoptosis in cultured HCC cells through ceramide production. Cinobufotalin may be investigated as a novel anti-HCC agent.

Shi J, He YY, Sun JX, et al.
The impact of sphingosine kinase 1 on the prognosis of hepatocellular carcinoma patients with portal vein tumor thrombus.
Ann Hepatol. 2015 Mar-Apr; 14(2):198-206 [PubMed] Related Publications
BACKGROUND: Though there is considerable evidence that sphingosine kinase 1(SPHK1) plays a key role in hepatocellular carcinoma(HCC) progression, the prognostic value of SPHK1 expression in HCC with portal vein tumor thrombus (PVTT) remains unclear. Aims. The purpose of this study was to investigate the relationship of SPHK1 expression with PVTT and HCC recurrence after hepatectomy.
METHODS: After screening of gene expression profiling of tumor cell lines, real-time PCR and immunohistochemistry were used to investigate the SPHK1 expression in PVTT and HCC samples. The clinical data of 199 HCC patients with nonmain PVTT who underwent liver resection with curative intention were studied.
RESULTS: We identified SPHK1 as the most over-expressed gene in PVTT via gene expression profiling of one human PVTT cell line (CSQT-2). SPHK1 expression was an independent factor affecting survival (hazard ratio [HR] 1.799, 95% confidence interval [CI] 1.337-2.368, P < 0.001) and tumor recurrence (HR 1.451, 95% CI 1.087-1.935, P = 0.011). Patients with SPHK1 over-expression had a poorer prognosis than those with SPHK1 under-expression (P < 0.001 and P = 0.011 for survival and tumor recurrence).
CONCLUSIONS: SPHK1 might represent a novel and useful prognostic marker of HCC progression in patients with PVTT.

Zhang L, Wang X, Bullock AJ, et al.
Anti-S1P Antibody as a Novel Therapeutic Strategy for VEGFR TKI-Resistant Renal Cancer.
Clin Cancer Res. 2015; 21(8):1925-34 [PubMed] Free Access to Full Article Related Publications
PURPOSE: VEGFR2 tyrosine kinase inhibition (TKI) is a valuable treatment approach for patients with metastatic renal cell carcinoma (RCC). However, resistance to treatment is inevitable. Identification of novel targets could lead to better treatment for patients with TKI-naïve or -resistant RCC.
EXPERIMENTAL DESIGN: In this study, we performed transcriptome analysis of VEGFR TKI-resistant tumors in a murine model and discovered that the SPHK-S1P pathway is upregulated at the time of resistance. We tested sphingosine-1-phosphate (S1P) pathway inhibition using an anti-S1P mAb (sphingomab), in two mouse xenograft models of RCC, and assessed tumor SPHK expression and S1P plasma levels in patients with metastatic RCC.
RESULTS: Resistant tumors expressed several hypoxia-regulated genes. The SPHK1 pathway was among the most highly upregulated pathways that accompanied resistance to VEGFR TKI therapy. SPHK1 was expressed in human RCC, and the product of SPHK1 activity, S1P, was elevated in patients with metastatic RCC, suggesting that human RCC behavior could, in part, be due to overproduction of S1P. Sphingomab neutralization of extracellular S1P slowed tumor growth in both mouse models. Mice bearing tumors that had developed resistance to sunitinib treatment also exhibited tumor growth suppression with sphingomab. Sphingomab treatment led to a reduction in tumor blood flow as measured by MRI.
CONCLUSIONS: Our findings suggest that S1P inhibition may be a novel therapeutic strategy in patients with treatment-naïve RCC and also in the setting of resistance to VEGFR TKI therapy.

Shou Y, Robinson DM, Amakye DD, et al.
A five-gene hedgehog signature developed as a patient preselection tool for hedgehog inhibitor therapy in medulloblastoma.
Clin Cancer Res. 2015; 21(3):585-93 [PubMed] Related Publications
PURPOSE: Distinct molecular subgroups of medulloblastoma, including hedgehog (Hh) pathway-activated disease, have been reported. We identified and clinically validated a five-gene Hh signature assay that can be used to preselect patients with Hh pathway-activated medulloblastoma.
EXPERIMENTAL DESIGN: Gene characteristics of the Hh medulloblastoma subgroup were identified through published bioinformatic analyses. Thirty-two genes shown to be differentially expressed in fresh-frozen and formalin-fixed paraffin-embedded tumor samples and reproducibly analyzed by RT-PCR were measured in matched samples. These data formed the basis for building a multi-gene logistic regression model derived through elastic net methods from which the five-gene Hh signature emerged after multiple iterations. On the basis of signature gene expression levels, the model computed a propensity score to determine Hh activation using a threshold set a priori. The association between Hh activation status and tumor response to the Hh pathway inhibitor sonidegib (LDE225) was analyzed.
RESULTS: Five differentially expressed genes in medulloblastoma (GLI1, SPHK1, SHROOM2, PDLIM3, and OTX2) were found to associate with Hh pathway activation status. In an independent validation study, Hh activation status of 25 medulloblastoma samples showed 100% concordance between the five-gene signature and Affymetrix profiling. Further, in medulloblastoma samples from 50 patients treated with sonidegib, all 6 patients who responded were found to have Hh-activated tumors. Three patients with Hh-activated tumors had stable or progressive disease. No patients with Hh-nonactivated tumors responded.
CONCLUSIONS: This five-gene Hh signature can robustly identify Hh-activated medulloblastoma and may be used to preselect patients who might benefit from sonidegib treatment.

Zheng XD, Zhang Y, Qi XW, et al.
Role of Sphk1 in the malignant transformation of breast epithelial cells and breast cancer progression.
Indian J Cancer. 2014 Oct-Dec; 51(4):524-9 [PubMed] Related Publications
BACKGROUND: The ojective of the following study is to investigate the role of sphingosine kinase 1 (Sphk1) in the malignant transformation of breast epithelial cells and breast cancer progression and its mechanism.
MATERIALS AND METHODS: Immunohistochemistry was performed to detect Sphk1 and E-cadherin (E-cad) in resected breast samples. Sphk1 was transfected in normal human breast epithelial cell line (MCF-10A) by Lentivirus and silenced in breast cancer cell line (MCF-7) using small interfering ribonucleic acid. The effect of tumor necrosis factor alpha (TNF-α) and/or N, N-dimethylsphingosine (DMS) on the Sphk1 and E-cad expression, MCF-10A cell proliferation and invasion was investigated. Real time-polymerase chain reaction and western-blot was used to detect messenger ribonucleic acid and protein. Cell counting kit-8 and transwell were used to measure cell proliferation and invasion.
RESULTS: Sphk1 was positive expression in 114 breast tumors (75.50%) but negative in fibroadenomas. The expression of E-cad and Sphk1 were negatively correlated and E-cad (-)/Sphk1 (+) carriers showed higher ratio of axillary lymph node metastasis than E-cad (+)/Sphk1 (-) carriers. Overexpression of Sphk1 in MCF-10A reduced E-cad expression and improved cell proliferation and invasion, but knockdown of Sphk1 in MCF-7 decreased cell proliferation and invasion. TNF-α increased Sphk1 expression, enhanced the ability of Sphk1 in decreasing E-cad expression, which could be blocked by DMS. TNF-α promoted MCF-10A cell proliferation and invasion.
CONCLUSION: Sphk1 plays an important role in the malignant transformation of breast epithelial cells and modulates breast cancer metastasis through the regulation of E-cad expression. TNF-α can up-regulate Sphk1 expression and reduce E-cad expression through Sphk1, which can be blocked by DMS. TNF-α/Sphk1/E-cad pathway may be a newly discovered pathway and plays an important role in tumorigenesis and metastasis.

Zhang K, Chen H, Wu G, et al.
High expression of SPHK1 in sacral chordoma and association with patients' poor prognosis.
Med Oncol. 2014; 31(11):247 [PubMed] Related Publications
Sacral chordoma is an aggressive bone tumor with a high local recurrence rate. Surgery remains the standard treatment because of its resistance to chemotherapy and radiotherapy. However, recurrence occurs frequently even after complete surgical resection. Great effort has been invested in discovering novel biomarkers and therapeutic targets. To date, the molecular mechanism is still unclear. In this study, we evaluated the expression of sphingosine kinase 1 (SPHK1) in 42 sacral chordoma samples and 16 distant normal tissue specimens by immunohistochemical staining. In addition, we analyzed its association with the clinical factors and patients' prognosis. Of all the chordoma samples, 69 % (29/42) showed high expression of SPHK1, whereas, only 19 % (3/16) of distant normal tissues expressed a high level of SPHK1 (p = 0.001). Chi-square analysis revealed that high expression of SPHK1 was significantly correlated with tumor recurrence (p = 0.019) and invasion into surrounding muscle (p = 0.005), while the data did not indicate any association with patients' gender, age, tumor location and size (p > 0.05). Kaplan-Meier survival curve and log-rank test showed that patients with high expression of SPHK1 possessed shorter continuous disease-free survival time. Conclusively, SPHK1 may become a potential biomarker for sacral chordoma in predicting its recurrence and patients' prognosis.

Datta A, Loo SY, Huang B, et al.
SPHK1 regulates proliferation and survival responses in triple-negative breast cancer.
Oncotarget. 2014; 5(15):5920-33 [PubMed] Free Access to Full Article Related Publications
Triple-negative breast cancer (TNBC) is characterized by unique aggressive behavior and lack of targeted therapies. Among the various molecular subtypes of breast cancer, it was observed that TNBCs express elevated levels of sphingosine kinase 1 (SPHK1) compared to other breast tumor subtypes. High levels of SPHK1 gene expression correlated with poor overall and progression- free survival, as well as poor response to Doxorubicin-based treatment. Inhibition of SPHK1 was found to attenuate ERK1/2 and AKT signaling and reduce growth of TNBC cells in vitro and in a xenograft SCID mouse model. Moreover, SPHK1 inhibition by siRNA knockdown or treatment with SKI-5C sensitizes TNBCs to chemotherapeutic drugs. Our findings suggest that SPHK1 inhibition, which effectively counteracts oncogenic signaling through ERK1/2 and AKT pathways, is a potentially important anti-tumor strategy in TNBC. A combination of SPHK1 inhibitors with chemotherapeutic agents may be effective against this aggressive subtype of breast cancer.

Xiong H, Wang J, Guan H, et al.
SphK1 confers resistance to apoptosis in gastric cancer cells by downregulating Bim via stimulating Akt/FoxO3a signaling.
Oncol Rep. 2014; 32(4):1369-73 [PubMed] Free Access to Full Article Related Publications
We previously reported that sphingosine kinase 1 (SphK1), an enzyme that catalyzes the production of sphingosine-1-phosphate (SIP), is upregulated in human gastric cancer and predicts poor clinical outcome. In the present study, we used known differential effects of UV irradiation on human MGC-803 gastric cancer cells to determine their effect on SphK1 activity. Ectopic expression of SphK1 in MGC-803 gastric cancer cells markedly enhanced their resistance to UV irradiation, whereas silencing endogenous SphK1 with shRNAs weakened this ability. Furthermore, these anti-apoptotic effects were significantly associated with decrease of Bim, an apoptosis-related protein. We further demonstrated that SphK1 could downregulate the transcriptional activity of forkhead box O3a (FoxO3a) by inducing its phosphorylation, which was found to be associated with the PI3K/Akt signaling. Taken together, our study supports the theory that SphK1 confers resistance to apoptosis in gastric cancer cells via the Akt/FoxO3a/Bim pathway.

Quint K, Stiel N, Neureiter D, et al.
The role of sphingosine kinase isoforms and receptors S1P1, S1P2, S1P3, and S1P5 in primary, secondary, and recurrent glioblastomas.
Tumour Biol. 2014; 35(9):8979-89 [PubMed] Related Publications
Sphingosine-1-phosphate (S1P), the corresponding kinases SphK1-2, and receptors S1P1-3 and S1P5 are involved in cell survival and growth. Pathway components are overexpressed in many tumors including glioblastoma. Previous studies showed that the expression of SphK1 influenced survival of glioblastoma patients, yet the roles of SphK1-2 and receptors S1P1-3 and S1P5 have not been investigated in different forms of glioblastoma. Samples from 59 patients (37 males, 22 females, age 55.1 ± 17.1 years) suffering from primary (n = 35), recurrent (n = 18), and secondary (n = 6) glioblastomas were analyzed using quantitative real-time PCR and immunohistochemistry for expression levels of SphK1 and SphK2 and S1P1-3 and S1P5. Sixteen autopsy nontumorous brain specimens were used as controls. Expression data was correlated with clinical data and patient survival. All markers were overexpressed in the glioblastoma specimens compared to the non-neoplastic brain tissue. SphK1 and all S1P receptors were expressed in increasing order of magnitude from primary, up to recurrent and secondary glioblastomas, with values of up to 44-fold compared to normal brain tissue. In contrast, SphK2 levels were highest in primary tumors (25-fold). Expression of the sphingosine signaling pathway components was influenced by radio/radiochemotherapy in distinct ways. Immunohistochemistry for SphK1 and S1P1 confirmed the overexpression in glioblastoma. Uni- and multivariate survival analyses identified S1P5 messenger RNA levels as an independent prognostic factor of survival. The sphingosine pathway is overexpressed in glioma. Its components show distinct expression patterns in the tumor subgroups. S1P5 is identified as an independent prognostic factor in multivariate analysis, and this pathway promises to be a candidate for targeted therapies.

Eberlein C, Rooney C, Ross SJ, et al.
E-Cadherin and EpCAM expression by NSCLC tumour cells associate with normal fibroblast activation through a pathway initiated by integrin αvβ6 and maintained through TGFβ signalling.
Oncogene. 2015; 34(6):704-16 [PubMed] Related Publications
Fibroblasts in the tumour stroma (cancer-associated fibroblasts) influence tumour progression and response to therapeutics; little is known about the mechanisms through which the tumour cell co-opts a normal fibroblast. To study the activation of fibroblasts by tumour cells, a panel of non-small cell lung cancer (NSCLC) cell lines and normal human dermal fibroblasts were co-cultured. A subset of the NSCLC cells induced an activated cancer-associated fibroblast-like fibroblast phenotype defined by induction of fibroblast α-smooth muscle actin expression. Tumour cells that activated fibroblasts were associated with E-Cadherin and EpCAM expression and expression of integrin αvβ6. Co-culture of activating tumour cells with fibroblasts resulted in induction of transcripts associated with tumour cell invasion and growth, TGFβ1 and TGFBR1, SERPINE-1, BMP6, SPHK1 and MMP9. Fibroblast activation was inhibited by an αvβ6/8 integrin blocking antibody (264RAD) and a small molecule inhibitor of the TGF-beta type I receptor activin-like kinase (ALK5) (SB431542), demonstrating that transactivation of the TGFβ pathway initiates fibroblast activation. Both integrin and ALK5 antagonists inhibited initiation. Only ALK5 was effective when added after 3 days of co-culture. This suggests that although activation is αvβ6-dependent, once fibroblasts are activated alternative TGFβ pathway regulators maintain an activation loop. In co-culture activating cells had reduced sensitivity to selumetinib, AZD8931 and afatinib compared with mono-culture. In contrast, non-activating cells were insensitive to selumetinib and AZD8931 in both mono-culture and co-culture. In conclusion NSCLC cell lines, positive for E-Cadherin, EpCAM and αvβ6 expression, activate normal fibroblasts through avβ6/TGFβ signalling in vitro, and influence both gene expression and response to therapeutic agents.

Martin JL, de Silva HC, Lin MZ, et al.
Inhibition of insulin-like growth factor-binding protein-3 signaling through sphingosine kinase-1 sensitizes triple-negative breast cancer cells to EGF receptor blockade.
Mol Cancer Ther. 2014; 13(2):316-28 [PubMed] Related Publications
The type I EGF receptor (EGFR or ErbB1) and insulin-like growth factor-binding protein-3 (IGFBP-3) are highly expressed in triple-negative breast cancer (TNBC), a particularly aggressive disease that cannot be treated with conventional therapies targeting the estrogen or progesterone receptors (ER and PR), or HER2. We have shown previously in normal breast epithelial cells that IGFBP-3 potentiates growth-stimulatory signaling transduced by EGFR, and this is mediated by the sphingosine kinase-1 (SphK1)/sphingosine 1-phosphate (S1P) system. In this study, we investigated whether cotargeting the EGFR and SphK1/S1P pathways in TNBC cells results in greater growth inhibition compared with blocking either alone, and might therefore have novel therapeutic potential in TNBC. In four TNBC cell lines, exogenous IGFBP-3 enhanced ligand-stimulated EGFR activation, associated with increased SphK1 localization to the plasma membrane. The effect of exogenous IGFBP-3 on EGFR activation was blocked by pharmacologic inhibition or siRNA-mediated silencing of SphK1, and silencing of endogenous IGFBP-3 also suppressed EGF-stimulated EGFR activation. Real-time analysis of cell proliferation revealed a combined effect of EGFR inhibition by gefitinib and SphK1 inhibition using SKi-II. Growth of MDA-MB-468 xenograft tumors in mice was significantly inhibited by SKi-II and gefitinib when used in combination, but not as single agents. We conclude that IGFBP-3 promotes growth of TNBC cells by increasing EGFR signaling, that this is mediated by SphK1, and that combined inhibition of EGFR and SphK1 has potential as an anticancer therapy in TNBC in which EGFR and IGFBP-3 expression is high.

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