Sphingosine kinase 1 plays a role in the upregulation of CD44 expression through extracellular signal-regulated kinase signaling in human colon cancer cells

Kawahara, Satomi; Otsuji, Yoko; Nakamura, Mitsuhiro; Murakami, Masashi; Murate, Takashi; Matsunaga, Toshiyuki; Kanoh, Hiroyuki; Seishima, Mariko; Banno, Yoshiko; Hara, Akira

doi:10.1097/cad.0b013e32835f705f

Cited by 23 publications

(16 citation statements)

References 39 publications

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“…Combination chemotherapy is an important strategy for improving therapeutic outcomes and reducing the side-effects of anticancer drugs. Various studies have indicated the possible utility of combining anticancer drugs with agents associated with the SK1/S1P pathway for cancer therapy (22)(23)(24). The combination of SK inhibitors, including siRNA, with anticancer drugs has been shown to be effective against drug-resistant colon cancer (22,23) and pancreatic cancer (24).…”

Section: Discussionmentioning

confidence: 99%

“…Various studies have indicated the possible utility of combining anticancer drugs with agents associated with the SK1/S1P pathway for cancer therapy (22)(23)(24). The combination of SK inhibitors, including siRNA, with anticancer drugs has been shown to be effective against drug-resistant colon cancer (22,23) and pancreatic cancer (24). The combination of doxorubicin and SK1-locked acid-antisense oligonucleotides has also been shown to be effective against gastric cancer (25).…”

Section: Discussionmentioning

confidence: 99%

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FTY720 and cisplatin synergistically induce the death of cisplatin-resistant melanoma cells through the downregulation of the PI3K pathway and the decrease in epidermal growth factor receptor expression

Ishitsuka

Fujine

Mizutani

et al. 2014

International Journal of Molecular Medicine

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Sphingosine kinase (SK), a key enzyme in sphingosine-1-phosphate (S1P) synthesis, is known to be overexpressed in various types of cancer cells. The effects of anticancer agents on SK1/S1P signaling have not yet been fully assessed in melanoma cells. In the present study, we investigated the effects of the combination of FTY720, an S1P receptor antagonist, and cisplatin, a DNA-damaging agent, on the induction of the death of human melanoma cells, as well as the molecular mechanisms involved. The viability of various human melanoma cell lines was examined following treatment with anticancer drugs. The cisplatin-resistant SK-Mel-28 and cisplatin-sensitive A375 cell lines were selected for this analysis. Protein expression and apoptotic rates were evaluated by western blot analysis following treatment with cisplatin and/or FTY720. Following treatment with a combination of FTY720 and cisplatin, cell viability significantly decreased and the expression of apoptosis-associated cleaved poly(ADP-ribose) polymerase (PARP) was significantly higher in comparison to treatment with cisplatin alone in the SK-Mel-28 cells. In addition, the combination of FTY720 and cisplatin reduced the protein expression of SK1 and the phosphorylation levels of phosphoinositide 3-kinase (PI3K), Akt and mTOR in the SK-Mel-28 cells; the expression of epidermal growth factor receptor (EGFR) was also markedly reduced. These findings suggest that FTY720 and cisplatin synergistically induce cell death through the downregulation of the PI3K/Akt/mTOR pathway and the decrease in EGFR expression in SK-Mel-28 cells. Thus, the combination of FTY720 and cisplatin may have therapeutic potential for chemotherapy-resistant melanoma, and the effects are likely exerted through the downregulation of S1P signaling.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

FTY720 and cisplatin synergistically induce the death of cisplatin-resistant melanoma cells through the downregulation of the PI3K pathway and the decrease in epidermal growth factor receptor expression

Ishitsuka

Fujine

Mizutani

et al. 2014

International Journal of Molecular Medicine

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“…In a model of colitis-associated cancer, S1P 1 signaling was necessary for persistent activation of nuclear factor-kB and signal transducer and activator of transcription3 transcription factors needed for maintaining the chronic infl ammatory state and could be blocked by FTY720 treatment ( 171 ). In human colon cancer cells, expression of the chemotherapeutic resistance and cancer stem cell marker CD44 was regulated by S1P 2 -induced ERK phosphorylation ( 172 ). Interestingly, FTY720 treatment impaired the mucosal immune response to the extracellular bacterium, Citrobacter rodentium , including decreased DC numbers, as well as macrophages and T cells in the colon, while increasing bacterial burden ( 173 ).…”

Section: Nervous Systemmentioning

confidence: 99%

An update on the biology of sphingosine 1-phosphate receptors

Blaho

Hla

2014

Journal of Lipid Research

439

403

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This article is available online at http://www.jlr.org during development and ageing. S1P 1 , S1P 2 , and S1P 3 are essentially ubiquitously expressed, whereas expression of S1P 4 and S1P 5 are highly restricted to distinct cell types ( 4 ).Production of S1P can be initiated by external or internal signals, which lead to activation of the biosynthetic pathway beginning with metabolism of membrane SM to ceramide by SMases ( 5, 6 ). Ceramide, an important signaling molecule itself, can be metabolized by ceramidase to sphingosine (Sph) ( 7 ). Sph is then phosphorylated by one of two Sph kinases (Sphks), Sphk1 or Sphk2, resulting in S1P genesis ( 8-10 ) ( Fig. 1 ).Although there are proposed intracellular roles for S1P, it is often transported out of the cell where it can act in an autocrine or paracrine manner on S1PRs ( 11, 12 ). Transport out of the cell may occur via several transporters; however, the only bona fi de transporter to date is spinster 2, which is also capable of FTY720 (fi ngolimod/Gilenya; Novartis) export (13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Once outside of the cell, S1P can bind to two known carriers, albumin or ApoM ( 6, 23, 24 ) ( Fig. 1 ). Approximately 35% of plasma S1P is bound to albumin and 65% to ApoM, which is found on a small percentage ( ‫ف‬ 5%) of HDL particles ( 24 ). This ApoM+HDL-bound S1P has been proposed as a primary contributor to the vasoprotective properties of HDLs ( 25-27 ). How albumin or ApoM deliver S1P to specifi c S1PRs has yet to be characterized. AGONISTS AND ANTAGONISTSThere are several well-characterized agonists and antagonists of S1PRs; however, most compounds have been diAbstract Sphingosine 1-phosphate (S1P) is a membranederived lysophospholipid that acts primarily as an extracellular signaling molecule. Signals initiated by S1P are transduced by five G protein-coupled receptors, named S1P 1-5 . Cellular and temporal expression of the S1P receptors (S1PRs) determine their specifi c roles in various organ systems, but they are particularly critical for regulation of the cardiovascular, immune, and nervous systems, with the most well-known contributions of S1PR signaling being modulation of vascular barrier function, vascular tone, and regulation of lymphocyte traffi cking. However, our knowledge of S1PR biology is rapidly increasing as they become attractive therapeutic targets in several diseases, such as chronic infl ammatory pathologies, autoimmunity, and cancer. Understanding how the S1PRs regulate interactions between biological systems will allow for greater effi cacy in this novel therapeutic strategy as well as characterization of complex physiological networks. Because of the rapidly expanding body of research, this review will focus on the most recent advances in S1PRs. Sphingosine 1-phosphate [2 S -amino-1-(dihydrogen phosphate)-4E-octadecene-1,3 R -diol] (S1P) is a simple membrane-derived lysophospholipid with regulatory roles in almost all facets of mammalian biology ( 1 ). Concentrations of S1P in blood and lymph plasmas are high, in the high...

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“…In colon cancer, S1PR1 is up-regulated by persistent activation of NF-KB and STAT3 transcription factors, resulting in colitis-associated colon cancer (Liang et al, 2013). In addition, S1PR2-induced ERK phosphorylation up-regulates CD44, a cancer stem cell marker in HCT116 human colon carcinoma cells (Kawahara et al, 2013). In prostate cancer, activity of S1PR5 induces autophagy through generating endoplasmic reticulum stress in human prostate cancer PC-3 cells (Huang et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Systemic distribution, subcellular localization and differential expression of sphingosine-1-phosphate receptors in benign and malignant human tissues

Wang

Mao

Redfield

et al. 2014

Experimental and Molecular Pathology

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Aims Five sphingosine-1-phosphate receptors (S1PR): S1PR1, S1PR2, S1PR3, S1PR4 and S1PR5 (S1PR1-5) have been shown to be involved in the proliferation and progression of various cancers. However, none of the S1PRs have been systemically investigated. In this study, we performed immunohistochemistry (IHC) for S1PR1-S1PR5 on different tissues, in order to simultaneously determine the systemic distribution, subcellular localization and expression level of all five S1PRs. Methods We constructed tissue microarrays (TMAs) from 384 formalin-fixed paraffin-embedded (FFPE) blocks containing 183 benign and 201 malignant tissues from 34 human organs/systems. Then we performed IHC for all five S1PRs simultaneously on these TMA slides. The distribution, subcellular localization and expression of each S1PR were determined for each tissue. The data were then compared in benign and malignant tissues from the same organ/tissue using the student t-test. In order to reconfirm the subcellular localization of each S1PR as determined by IHC, immunocytochemistry (ICC) was performed on several malignant cell lines. Results We found that all five S1PRs are widely distributed in multiple human organs/systems. All S1PRs are expressed in both the cytoplasm and nucleus, except S1PR3, whose IHC signals are only seen in the nucleus. Interestingly, the S1PRs are rarely expressed on cellular membranes. Each S1PR is unique in its organ distribution, subcellular localization and expression level in benign and malignant tissues. Among the five S1PRs, S1PR5 has the highest expression level (either in nucleus or cytoplasm), with S1PR1, 3, 2 and 4 following in descending order. Strong nuclear expression was seen for S1PR1, S1PR3 and S1PR5, whereas S1PR2 and S1PR4 show only weak staining. Four organs/tissues (adrenal gland, liver, brain and colon) show significant differences in IHC scores for the multiple S1PRs (nuclear and/or cytoplasmic), nine (stomach, lymphoid tissues, lung, ovary, cervix, pancreas, skin, soft tissues and uterus) show differences for only one S1PR (cytoplasmic or nuclear), and twenty three organs/tissues show no significant difference in IHC score of any S1PR (cytoplasmic or nuclear) between benign and malignant changes. Conclusion This is the first study to evaluate the expression level of all S1PRs in benign and malignant tissues from multiple human organs. This study provides data regarding the systemic distribution, subcellular localization and differences in expression of all five S1PRs in benign and malignant changes for each organ/tissue.

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Sphingosine kinase 1 plays a role in the upregulation of CD44 expression through extracellular signal-regulated kinase signaling in human colon cancer cells

Cited by 23 publications

References 39 publications

FTY720 and cisplatin synergistically induce the death of cisplatin-resistant melanoma cells through the downregulation of the PI3K pathway and the decrease in epidermal growth factor receptor expression

FTY720 and cisplatin synergistically induce the death of cisplatin-resistant melanoma cells through the downregulation of the PI3K pathway and the decrease in epidermal growth factor receptor expression

An update on the biology of sphingosine 1-phosphate receptors

Systemic distribution, subcellular localization and differential expression of sphingosine-1-phosphate receptors in benign and malignant human tissues

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