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Year : 2013  |  Volume : 9  |  Issue : 4  |  Page : 556-563

Sphingosin 1-phosphate contributes in tumor progression

1 Department of Medical Biotechnology, Faculty of Advanced Medical Sciences; Research Center for Pharmaceutical Nanotechnology; Student Research Center Committee, Tabriz University of Medical Sciences, Tabriz, Iran
2 Department of Medical Biotechnology, Faculty of Advanced Medical Sciences; Research Center for Pharmaceutical Nanotechnology; Department of Biochemistry and Clinical Laboratories, Tabriz University of Medical Sciences, Tabriz, Iran
3 Department of Medical Biotechnology, Faculty of Advanced Medical Sciences; Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran
4 Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran
5 Department of Infecious Disease, Tabriz University of Medical Sciences, Tabriz, Iran

Date of Web Publication11-Feb-2014

Correspondence Address:
Nasser Samadi
Department of Medical Biotechnology, Faculty of Advanced Medical Sciences and Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz
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Source of Support: Research Center for Pharmaceutical Nanotechnology, Tabriz University of Medical Sciences, Tabriz, Iran, Conflict of Interest: None

DOI: 10.4103/0973-1482.126446

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 > Abstract 

Sphingosine-1 phosphate (S1P) is a bioactive lipid that mediates diverse cellular responses. Signaling of S1P is carried out by a family of G-protein coupled receptors (GPCRs), which show differential expression patterns depending on tissue and cell types. Activation of S1P receptors induces signaling pathway, which can subsequently lead to physiological process. Intercellular S1P concentration is regulated and determined by several enzymes including S1P lyase, S1P kinase and S1P phosphatase. Numerous studies showed the role of S1P in malignant behavior of cancer cells including breast, lung, colon, and leukemia cell lines. In the past decade, extensive research activities have focused on elucidating S1P signaling pathway, its receptors, enzymes involved in S1P metabolism, and its performance in cancer biology. In this review, we will explain the function of S1P in tumor progression that demonstrated in past research articles and we will express its importance as a target for designing futuristic anticancer drug.

Keywords: Chemoresistance, metastasis, proliferation, sphingosine-1 phosphate

How to cite this article:
Tabasinezhad M, Samadi N, Ghanbari P, Mohseni M, Saei AA, Sharifi S, Saeedi N, Pourhassan A. Sphingosin 1-phosphate contributes in tumor progression. J Can Res Ther 2013;9:556-63

How to cite this URL:
Tabasinezhad M, Samadi N, Ghanbari P, Mohseni M, Saei AA, Sharifi S, Saeedi N, Pourhassan A. Sphingosin 1-phosphate contributes in tumor progression. J Can Res Ther [serial online] 2013 [cited 2020 Sep 28];9:556-63. Available from: http://www.cancerjournal.net/text.asp?2013/9/4/556/126446

 > Introduction Top

In recent years, researches on lipids have shifted from their constitutive roles in the cell membrane to the signaling aspect of these molecules. We read several research articles about Sphingosine-1 phosphate (S1P), its mechanisms, process of S1P synthesis and degradation, their receptors and function, effects of S1P in different cancer cell, and subsequently gather this data in this literature review to express the importance of this lipid.

Sphingolipids are ubiquitous components of eukaryotic cell membranes, which can be metabolized to ceramide, sphingosine, and their phosphorylated forms such as ceramide 1-phosphate (C1P) and S1P that possess bioactivity and vital biological function in cell growth and survival. [1]

Experimental studies have denoted S1P as one of the most important sphingolipid metabolites. [2] S1P plays various roles in physiological process, promotes cellular proliferation, stimulates cell survival, and protects cells against apoptosis through G-protein coupled receptors (GPCRs) or an intracellular receptor-independent mechanism. [3],[4]

Intracellular S1P level is regulated with S1P lyase (SPL), S1P kinase (SphK), and S1P phosphatase (SPP1-SPP2) and alteration in one of these enzymes can change S1P levels and result in cells survival or death. [5] Balance between synthesis and degradation of S1P is firmly regulated by these three enzymes. [6]

Modulation of normal S1P level in blood or tissues can contribute to pathophysiologic events in cardiovascular diseases, chronic inflammation, cancer, drug resistance, and metastasis. [4],[7],[8],[9],[10],[11],[12],[13] Recently, extensive insight has been gained on S1P signaling pathways, its receptors, enzymes involved in S1P metabolisms, and S1P performance in cancer biology; however, further studies are required to reveal S1P roles in tumor progression. In this review, we will explain the function of S1P in tumor malignancy and finally, we will express the importance of this molecule in designing futuristic targeted anticancer chemotherapeutics.

Biochemistry of S1P

A long-chain base is one of the most obvious characteristics of sphingolipids, which has the potential to be phosphorylated or acrylated at the free amino group. [1] S1P the ATP-dependent phosphorylated form of sphingosine can only be produced from sphingosine by two sphingosine kinases (SphK1-SphK2). [14] The two isoforms of SphK have different properties and substrate selectivity [15] are differentially distributed in different tissues. [16] SphK1 is responsible for S1P presence in blood [17] and more selective than SphK2. [17] As a consequence, SphK1 can prove a better target in therapy of S1P-related diseases. S1P phosphatase dephosphorylates S1P to sphingosine and ultimately sphingosine lyase degrades S1P to hexadecenal and ethanolamine-phosphate. [18] Contrary to S1P, which contributes to cell survival, ceramide is another signaling molecule that can induce apoptosis and produced through sphingolipid turnover. [19] Acylation of sphingosine and other long-chain base sphingolipids lead to formation of ceramide in turnover pathway. [20] On one hand, sphinogmylinase converts sphingomylin to ceramide and on the other ceramidase alters ceramide to sphingosine. [21] Overall, these processes regulate the equilibrium between cell survival and death. [21]

Physiology of S1P

S1P has been found in numerous mammalian cells and other organisms and harbors distinctive biological functions. [22] S1P can be found in blood in nM levels and binds albumin. [23] The concentration of S1P in lymph and tissues is about 4- to 5-fold and 1000-fold lower than blood, respectively. [12] The higher concentration of S1P in circulation compared with tissues results from high generation of S1P by hematopoietic cell lines. [12],[24] In addition, many different cells can synthesize S1P and transport it to plasma by efflux systems such as ABC transporters. [25],[26] Several extracellular molecules such as pro-inflammatory cytokines, growth factors, hormones, some GPCR ligands, and even S1P itself [27],[28] can induce intracellular signaling cause activation of kinases that phosphorylate SphK1 and activate it, so that it translocates from cytosol to cell membrane and phosphorylates sphingosine to S1P. [29]

S1P as a first messenger

The intracellular S1P effluxes to the extracellular environment by ATP-binding cassette transporters ABCA1, ABCC1, and ABCG2, [30],[31],[32] subsequently attaches to associated GPCRs on auto cell or others and leads to signal transductions involved in regulation of growth, motility, and survival [Figure 1]. [26] These transporters are responsible for the autocrine and paracrine activity of S1P. [26] S1P-activated GPCRs are coupled to G i , G q , or G 12/13 and induce different downstream signaling pathway. [33] Interestingly, signal transduction of G i -protein is susceptible to pertussis toxin (PTX), which is known to inhibit G i protein by G i ADP-ribosylate and activate of adenylyl cyclase. [33]
Figure 1: S1P signaling. Various ligands such as cytokines and growth factors attach to their receptors and activate Sphk1. Then SphK1 moves to cell membrane and phosphorylates Sphingosin to construct S1P. S1P releases to cytoplasm and mediates cell survival or transport to extracellular via ABC-transporters and acts on auto cells (autocrine pathway) or another cell (paracrine pathway) via activation of different S1PRs and play key role in cell survival, proliferation, migration, angiogenesis, and chemoresistance

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G-protein coupled to S1P

Results from various studies have indicated that various activity of S1P induce through S1PRs (S1P receptors) by coupling the specific G i -proteins and mediate several physiologic process [Table 1]. S1P1 is coupled to Gi and ribosylate adenylyl cyclase, activates Ras/MAPK pathway, [34] activates PI3K/AKt endothelial nitric oxide (eNO) pathway, [35] and activates phospholipase C (PLC)/IP3 independent Ca 2+ release. [36] S1P2 can also couple to G i , G q , and G 12/13 . [33] S1P2 linkage to G i triggers downstream signaling of PTX-dependent ERK/MAPK as well PLC/PI3/Ca 2+ , [37] Rho family, [38] p38, Jun N-terminal kinase (JNK), MAP kinases, [38] and phospholipase D activation, [39] which is similar to S1P2, S1P3, link to G i , G q , and G 12/13 . [33] Although these receptors have different biological functions, [40] but both of them are able to induce nuclear factor (NF)-κB pathway by G q . [41] S1P3 and S1P1 are more capable for linkage of G i than S1P2, [42] however, S1P2 is more potent to activate Rho pathway via couples to G12/13. [40],[43] In addition, S1P4 binds to G i and G 12/13 , but never binds to G q . [44] S1P4 activates PLC, ERK, and the Rho family and development of peripheral stress fibers and cell rounding and mediates various intracellular functions. [45],[46] Same as S1P4, S1P5 attaches to only G i and G 12/13 , [47] but unusually, G i activation by S1P5 represses the ERK1/2. [47] This is while S1P5 induces JNK/MAPK and does not activate of p38 signaling. [47]
Table 1: S1P induces various signaling pathways by attaches to different S1P-receptors (S1P1-S1P5) and activates GPCRs

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S1P as a second messenger

Intracellular S1P can act as a second messenger, [48] possibly by binding to a variety of intracellular targets "directly." [49] As mentioned earlier, various extracellular signals triggered by hormones, growth factors, and many cytokines such as PDGF, epidermal growth factor, TNF-K, and nerve growth factor can activate SphK and enhance intracellular S1P levels, which are in turn involved in various biological functions such as cell proliferation, survival, and inhibition of apoptosis. [50],[51]

Principal functions of S1P

Mitogenesis is the first physiological role associated to S1P in the early 1990s. [52] Primary function of S1P is involvement in promotion of cell proliferation in various cells including fibroblasts, [52] osteoblasts, [53] endothelial cells, [54] intestinal epithelial cells, [55] hepatic satellite cells, [56] and neural progenitor cells. [57] Cell progression is one of the intracellular phenomena that regulates by phosphorylation and activation of SphK through extracellular signals. [58] SphK activates results in production of S1P, which subsequently generates proliferative and antiapoptotic signals. [58]

Alike S1P1, S1P3 induce antiapoptotic signal by S1P activation and is thus involved in cell motility and regulation of cytoskeleton rearrangement. [59],[60] On the contrary to S1P1 and S1P3, which stimulate of cell migration, S1P2 inhibits this process. [61] Consequently S1P plays a reciprocal role in cell migration through activation of diverse GPCRs in different cell types. [59] There is little evidence to define the specific roles of S1P4 and S1P5. [46],[62],[63] S1P induces chemotacsis in endothelial cells and accordingly angiogenesis through S1P1 and S1P3 pathways, [64],[65] although S1P2 inhibit endothelial cells migration and angiogenesis. [66] Finally, S1P by binding to S1P5 inhibit extracellular signals that regulate kinase (ERK) activation. [67] This process contributes to reduction of cell proliferation in cells that overexpress S1P5 [47] including oligodendrocytes and astrocytes. [68]

Deregulation of S1P and cancer

As explained earlier, S1P has a key role in various biological processes. Alterations in expression of S1PRs, ABC transporter, and the enzymes interfering in S1P metabolism result in progression of some disease [69],[70],[71],[72],[73] and various types of cancer. [74] Different functions of S1P in cell biology and its involvement in the pathology of a number of diseases made researchers around the world to study this bioactive lipid and its downstream pathways to overcome different types of cancer.

S1P in cell survival

Balance between the concentration of ceramide and S1P is critical for cell fate. [75] Thus, deregulation of this equilibrium result in cell survival and inhibition of apoptotic pathway and has already been shown in cases with colon carcinomas. [76] As a result, processes that augment endogenous ceramide levels, including agonists of sphingomylinase may be implicated in cancer therapy. [77] Moreover, increased expression of Sphk1 has been noted in various type of cancer including colon, breast, gastric, and kidney [Figure 1]. [78] Some studies have implicated S1P in induction of antiapoptotic MAP kinase and impediment of pro-apoptotic MAP kinase pathway in U937 leukemia cells [79] and its cyto-protective role in HL-60 cells. [80] S1P reduced pro-apoptotic Bax and protected T lymphoblastoma cell line Tsup-1 from apoptotic cascades mediated by ceramide and Fas ligand. [81]

Overexpression of S1P3 or S1P2 in HTC4 hepatoma cells after treatment with S1P in starving media protected them from apoptosis. [82] Elevated SphK1 expression is associated with bad prognosis in glioblastoma multiforme [83] and breast cancer patients, [84] as well reduced apoptosis in HL-60 acute myeloid leukemia cells. [85] Similarly, pro-survival effects of S1P are mediated through prevention of cytochrome c and Smac/DIABLO release from mitochondria and subsequent inhibition of activation of caspase-3 in the human acute leukemia Jurkat, U937, and HL-60 cell lines. [86] Protective role of S1P in ovarian cancer cells is carried out by activation of Akt through S1P1 or S1P3. [87] In a similar manner in T lymphoblastoma cells, S1P inhibits apoptosis through S1P2 and S1P3 signaling and reduces the expression of pro-apoptotic protein Bax. [81]

S1P in cell proliferation

Overexpression of SphK1 and subsequent release of high levels of S1p from tumor cells facilitates tumor progression through autocrine activation of S1PRs [Figure 1]. [49] S1P-dependent tumor progression has been found in many cancer cells including malignant ovarian cancer patients, [88] mice model intestinal polyp, [89] MCF-7 breast cancer in vitro, and in mice model, [90] mice injected with prostate cancer cell [91],[92] PC12, pheochromocytoma cells [93] and human melanoma cells. [94] Furthermore, downregulation of Sphk1 by inhibitors, activates apoptotic pathways and decreases tumorgenesis in cancer cell line including prostate cancer cells, gastric, lung, and mammary adenocarcinoma tumor growth in mice. [95],[96],[97] Alterations in other S1P catabolic enzymes such as SPL and SPP, also plays an important role in cancer proliferation and downregulation of these enzymes have been found in human colon cancer. [89] Tumor proliferations results from extracellular effect of S1P, which is mediated through GPCRs, this pathway has been implicated in human glioblastoma, [98] gastric cancer, [24] thyroid cancer, [99] and ovarian cancer. [100] In addition, S1P attributes to cell proliferation through S1P1, S1P3, and S1P2 receptors in glioblastoma cell line U-373, [98] while S1P5 blocks proliferation of this cell line. [101]

S1P in tumor invasion, migration and metastasis

One remarkable function of S1P is contribution to tumor metastasis by modifying extracellular environment and induction of invasion, motility, and migration of cells to other locations. [102] In addition, these effects of S1P are mediated via receptor-dependent pathways that activate different receptors and attribute to diverse effects in various cell lines as we explain later. Hence, S1P1, S1P3, and S1P5 activate cell migration [Figure 1] through Rac and PLC signaling, despite the fact that S1P2 plays an antimigration effect by Rho signaling. [103] Degradation of extracellular matrix by matrix metalloproteinases (MMPs), a zinc-dependent proteolytic enzyme initiates cell migration. [103] Similarly, S1P causes overexpression of MMP-2 through the MAPK kinase/ERK and NF-κB pathways and is responsible for invasion in human umbilical vein endothelial cells (HUVECs) and EAby925 endothelial cells. [104] In contrast, inhibition of these enzymes reduces cell invasion. [104]

Upregulation of S1P can also lead to overexpression of MMP2 that has a major role in initiating cell invasion via H-Ras signaling in MCF10A human breast cancer. [105] Moreover, high levels of MMP9 induced by S1P, stimulates cell invasion via S1P3 in MCF10A cells. [61] Antimigratory effect of S1P/S1P2 mediated through RhoA/Rho-kinase cascade has also been shown in glioblastoma cells. [106] Research on B16 mouse melanoma cells has shown S1P/S1P2 signaling result in antimigratory and antiinvasive effects. [107] Morover, S1P/S1P1 signaling in these cells enhances cell migration and metastasis. [108] It can be inferred that S1P role in cell migration is dependent on the type of cells and their corresponding receptors. The effects of S1P in metastasis including cell migration and invasion have been shown in epithelial ovarian cancer, [109] breast carcinomas, [110] ML-1 thyroid carcinoma cells, [111] Wilms tumor, [112] and OVCAR3 ovarian cancer cells [113] that are mediated through S1P1 or S1P3. [114] Studies have found overexpression of S1P3, which lead to cell migration in gastric cancer cells lines, however, S1P2 plays inverse roles in these cell lines. [24] Additionally, alterations in SphK1 and SphK2 levels have significant effects on the migration of MDA-MB-453 breast cancer cells; therefore, overexpression of SphKs has positive effects on cell migration and decreases SphKs levels. [115]

S1P in angiogenesis

Angiogenesis is one of critical phenomenon for growth and metastasis in solid tumor [116] and numerous studies have demonstrated the role of S1P in angiogenesis through different mechanisms as we explain as follows. S1P stimulates migration of endothelial cells [63] and vascular smooth muscle cells [117],[118] and promotes the construction of capillary-like tube via bovine aortic endothelial cells to create new blood vessels. [63] S1P1 gene deficiency in mice causes hemorrhage because of incomplete maturation of vascular system and confirms the claim that pro-angiogenic effect of S1P is mediated through S1P1 signaling [Figure 1]. [119] In addition to angiogenic induction by S1P1, S1P promotes angiogenesis by upregulation of endothelial differentiation gene-1 (EDG-1) and EDG-3 and vascular endothelial growth factor (VEGF) in endothelial cells [120],[121] as well as improvement of DNA synthesis in HUVECs. [122]

In addition, regulation of S1P1 via VEGF mediates the crosstalk between VEGF and S1P1, which has an important role in vascularization and angiogenesis. [121] Both extracellular and intracellular signaling of S1P [119] as well as the crosstalk between S1P and other pro-angiogenic growth factors such as VEGF, EGF, PDGF, bFGF, and IL-8 are involved in this process. [123] Furthermore, stimulation of SphK1 via VEGF induction enhances the intracellular levels of S1P and mediates S1P receptor-independent extracellular effects that have been shown in T24 bladder tumor cells. [124] Research has also demonstrated that S1P upregulates VEGF in human prostate cancer PC-3 cells. [103] Remarkable overexpression of S1P1 has been noted in tumor vessels so injection of S1P1 siRNA in murine tumor models diminished tumor vascularization, angiogenesis, and subsequently tumor progression in vivo. [125] Inhibition of S1P1 in vitro, blocks the pro-angiogenic effect of S1P. [126] Induction of angiogenesis via S1P has been reported in endothelial cells, [127] thyroid cancer, [128] and breast cancer cells. [129] Upregulation of SphK1 in U87 glioma cells lead to enhancement of neovascularization [130] and in MCF-7 cell increases microvessel density around the tumor. [90] In xenograft model of Lewis lung carcinoma, injections of anti-S1P1 siRNA reduced tumor angiogenesis, neoangiogenesis, and finally decrease the tumor progression to a great extent. [125]

S1P in chemoresistance

Different sphingolipid metabolites potentially induce either anticancer signaling or attribute to cell survival by induction of chemoresistance to anticancer agents. This effect has been noted in many types of cancer such as pancreas, [131] and acute myeloid leukemia. [132] More studies have shown the correlation between SphK1 and S1P in chemoresistance due to ceramide/S1P imbalance. [58] Overexpression of SphK1 decreases the sensitivity of A-375 melanoma cells to ceramide therefore attenuates apoptotic signal, however, A-375 cells death is initiated by inhibition of this enzyme. [94] Upregulation of SphK1 and S1PRs were seen in PC3 prostate cancer cells resistant to camptothecin (CPT). [91] In addition, targeting the SphK1 or S1PRs signaling result in stimulation of cell death in PC3 cells treated with CPT. [91],[133],[134]

In HL-60 leukemia cell lines, upregulation of SphK1 inhibits doxorubicin or taxotere-induced apoptosis. [85] Depletion of S1P lyase caused cisplastin resistance. [135] Furthermore, multidrug resistance (MDR) in cancer chemotherapy is one of the most common reasons to deterioration of patient prognosis. [136] MDR-associated protein (MRP-1) and P-glycoprotein (Pgp) are members of this family. [137] In addition, S1P can affect the activity of Pgp through activation of S1P1 or S1P3 in brain tumor-derived endothelial cells [Figure 1]. [137] It is also interesting that reported chemoresistant or MDR-1 positive HL-60 cells demonstrated infinite SphK1 activity that reduce ceramide generation during drug treatment. [132] In contrast, chemosensitive HL-60 cell lines can inhibit SphK1 and enhance ceramide production, [85] furthermore, similar results have been shown in chemoresistance and chemosensitive prostate cancer cells treated via docetaxel or camptothecin. [92] Investigations have revealed SphK1 inhibitor compounds as F-12509a and B-5354c capable of blocking S1P biosynthesis and ceramide generation in chemoresistant cells. [138] In accordance with these studies, F-12509a stimulates apoptosis in MDR-1 positive HL-60 cells that are resistant to doxorubicin or VP16. [85] In the chronic myeloid leukemia LAMA cell line, F-12509a mediates caspase-3-dependent apoptosis by decreasing the S1P and increasing the ceramide level in imatinib-resistant cells. [139] Finally, the B-5354c is able to initiate apoptosis via decreasing SphK1 and enhancing ceramide levels in chemoresistant prostate cancer cells as docetaxel resistant LNCaP and camptothecin-resistant PC-3. [91],[140] In conclusion, SphK1/S1PRs plays a vital role in induction of cancer chemoresistance.

Concluding remark

Due to the role of S1P in proliferation, migration, and invasion of cancer cells in the past decade, extensive studies have been done on S1P signaling pathways, its receptors, the enzymes involved in S1P metabolisms, and S1P performance in cancer biology. However, further studies are required to reveal the detailed information about S1P-dependent signaling pathways in initiation and formation of tumor, metastasis, and chemo-resistance. In this review, we explained the function of S1P in tumor progression and we also described the importance of this molecule as a target to design novel anticancer drugs in future.

[TAG:2]Acknowledgment [/TAG:2]0

The authors apologize to colleagues whose work has not been mentioned here due to space limitations. This work was supported by Research Center for Pharmaceutical Nanotechnology.

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