S1P and LPA have an attachment-dependent regulatory effect on invasion of epithelial ovarian cancer cells

Smicun, Yoel; Gil, Orlando D.; Devine, Kate; Fishman, David A.

doi:10.1016/j.ygyno.2007.06.024

Cited by 35 publications

(23 citation statements)

References 44 publications

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“…Our previous data also demonstrated that attached and invading cells represent two very different functional states, with contrasting presentation of adhesion molecules [26]. The current study is consistent in that gelatinase and uPA activities secreted by invading cells are many fold higher than activities secreted by attached cells.…”

Section: Discussionsupporting

confidence: 89%

“…The effect of S1P on these enzymes and adhesion molecules are significantly altered by the inhibition of Gi and Rac, giving us new information about the Edg-coupled pathways that influence EOC invasion. Our previous finding that invading cells respond differently from attached cells [26] was reinforced by this study: gelatinase and uPA activities were significantly increased in the conditioned media of invading versus attached cells, indicating the important role of proteolysis in invasion. In aggregate, these results appear to demonstrate that uPA activity in invading cell conditioned media correlates with Rac-dependent S1P regulation of DOV 13 cell invasion.…”

Section: Discussionsupporting

confidence: 75%

“…We previously found that the effects of S1P and LPA on invasion of Dov 13 cells inversely correlated with their effects on the expression of N-cadherin in the cell membrane [26]. We further evaluated effects of S1P and LPA on the distribution of N-cadherin on the cell surface using immunofluorescence, as both previously demonstrated induction of invasion and suppression of surface N-cad in Dov-13 cells [26].…”

Section: Low S1p Concentrations and Lpa Induce Clustering Of Membranementioning

confidence: 91%

“…We further evaluated effects of S1P and LPA on the distribution of N-cadherin on the cell surface using immunofluorescence, as both previously demonstrated induction of invasion and suppression of surface N-cad in Dov-13 cells [26]. Membrane-N-cadherin (m-N-cad) was visible in all cells regardless of treatment (figure 5).…”

Section: Low S1p Concentrations and Lpa Induce Clustering Of Membranementioning

confidence: 97%

“…N-cadherin is present in the membranes of DOV 13 cells, while OVCA 429 membranes contain E-cadherin. We recently found that DOV 13 membrane-Ncadherin was increased by high concentration S1P (20µM) and reduced by LPA [26]. The inverse correlation observed between SIP and LPA's effects on membrane-N-cadherin and invasiveness suggests that membrane presentation of N-cadherin and its related cell-cell attachment may constitute another mechanism by which these phospholipids regulate EOC invasion and migration.…”

Section: Introductionmentioning

confidence: 99%

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S1P induced changes in epithelial ovarian cancer proteolysis, invasion, and attachment are mediated by Gi and Rac

Devine

Smicun

Hope

et al. 2008

Gynecologic Oncology

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OBJECTIVES-We previously demonstrated that sphingosine 1-phosphate (S1P) bimodally regulates epithelial ovarian cancer (EOC) cell invasiveness: low-concentration S1P stimulates invasion similar to lysophophatidic acid (LPA), while high-concentration S1P inhibits invasion. In this study, we investigated the mechanisms through which S1P affects EOC cell proteolysis, invasion, and adhesion in two cultured epithelial ovarian cancer cell lines. METHODS-G-proteinGi was inhibited by pertussis toxin (PTX) and GTP binding protein Rac by NSC23766. S1P conditioned media of DOV13 and OVCA429 cells were evaluated via gel zymography, fluorometric gelatinase assay, urokinase plasminogen activator (uPA) activity assay, and Western Blot for MT1-MMP. Cell invasion was analyzed in Matrigel chambers. Membrane-N-cadherin was localized via fluorescence microscopy.RESULTS-Zymography revealed pro-MMP2 in conditioned media of EOC cells regardless of treatment. Gelatinase activity was increased by low-concentration S1P. In DOV13 cells this effect was Gi and Rac dependent. In all OVCA429 and control DOV13 cells, PTX enhanced gelatinolysis, suggesting an MMP2-inhibitory pathway via Gi. MT1-MMP was decreased Gidependently by high-concentration S1P. Rac inhibition significantly counteracted low-S1P enhancement and high-S1P reduction of DOV13 invasiveness; and uPA activity in conditioned media of invading cells correlated significantly. Immunohistochemistry revealed Gi-dependent clustering of membrane-N-cadherin in DOV13 cells treated with 0.5µM S1P or 10µM LPA.CONCLUSIONS-S1P influences EOC invasion by regulating ECM-proteolysis and cell-cell attachment via MMP2, uPA, and membrane-N-cadherin. Furthermore, this study illustrates that the net effect of S1P on each of these processes reflects a complex interplay of multiple GPCR pathways involving Gi and downstream Rac.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 75%

Section: Low S1p Concentrations and Lpa Induce Clustering Of Membranementioning

confidence: 91%

Section: Low S1p Concentrations and Lpa Induce Clustering Of Membranementioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

S1P induced changes in epithelial ovarian cancer proteolysis, invasion, and attachment are mediated by Gi and Rac

Devine

Smicun

Hope

et al. 2008

Gynecologic Oncology

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Sphingolipid metabolism in the development and progression of cancer: one cancer's help is another's hindrance

2021

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Cancer development is a multistep process in which cells must overcome a series of obstacles before they can become fully developed tumors. First, cells must develop the ability to proliferate unchecked. Once this is accomplished, they must be able to invade the neighboring tissue, as well as provide themselves with oxygen and nutrients. Finally, they must acquire the ability to detach from the newly formed mass in order to spread to other tissues, all the while evading an immune system that is primed for their destruction. Furthermore, increased levels of inflammation have been shown to be linked to the development of cancer, with sites of chronic inflammation being a common component of tumorigenic microenvironments. In this Review, we give an overview of the impact of sphingolipid metabolism in cancers, from initiation to metastatic dissemination, as well as discussing immune responses and resistance to treatments. We explore how sphingolipids can either help or hinder the progression of cells from a healthy phenotype to a cancerous one.

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Lysophospholipid Signaling in Female and Male Reproductive Systems

2013

Lysophospholipid Receptors

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S1P and LPA have an attachment-dependent regulatory effect on invasion of epithelial ovarian cancer cells

Cited by 35 publications

References 44 publications

S1P induced changes in epithelial ovarian cancer proteolysis, invasion, and attachment are mediated by Gi and Rac

S1P induced changes in epithelial ovarian cancer proteolysis, invasion, and attachment are mediated by Gi and Rac

Sphingolipid metabolism in the development and progression of cancer: one cancer's help is another's hindrance

Lysophospholipid Signaling in Female and Male Reproductive Systems

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