Sphingosine 1-phosphate regulates matrix metalloproteinase-9 expression and breast cell invasion through S1P3–Gαq coupling

Abstract

SummaryRecent evidence suggests that inflammation is involved in malignant progression of breast cancer. Sphingosine 1-phosphate (S1P), acting on the G-protein-coupled receptors, is known as a potent inflammatory mediator. In this study, the effect of the inflammatory lipid S1P on the regulation of invasive/migratory phenotypes of MCF10A human breast epithelial cells was investigated to elucidate a causal relationship between inflammation and the control of invasiveness of breast cells. We show that S1P causes induction of matrix metalloproteinase-9 (MMP-9) in vitro and in vivo, and thus enhances invasion and migration. We also show that fos plays a crucial role in the transcriptional activation of MMP-9 by S1P. In addition, activation of extracellular-signal-regulated kinases 1 and 2 (ERK1/2), p38 and alpha serine/threonine-protein kinase (Akt) are involved in the process of S1P-mediated induction of MMP-9 expression and invasion. Activation of the S1P receptor S1P 3 and G q are required for S1P-induced invasive/migratory responses, suggesting that the enhancement of S1P-mediated invasiveness is triggered by the specific coupling of S1P 3 to the heterotrimeric G q subunit. Activation of phospholipase C- 4 and intracellular Ca 2+ release are required for S1P-induced MMP-9 upregulation. Taken together, this study demonstrated that S1P regulates MMP-9 induction and invasiveness through coupling of S1P 3 and G q in MCF10A cells, thus providing a molecular basis for the crucial role of S1P in promoting breast cell invasion. Journal of Cell Science cell systems. S1P induces invasion of human endothelial cells and HT1080 fibrosarcoma cells by regulating MMP-2 or MT1-MMP (Wu et al., 2005; Fisher et al., 2006). In contrast, the inhibitory role of S1P in IL--induced MMP-9 expression has been shown in mesangial cells (Xin et al., 2004).In an attempt to elucidate the molecular link between inflammation and breast cancer progression, the present study investigated the effect of an inflammatory lipid S1P on the invasive program of breast epithelial cells. Although the induction of mammary epithelial cell invasion occurs as a normal physiological process during pregnancy when the gland expands in preparation for lactation (Traurig, 1967), an invasive phenotype has been shown to induce the expression of MMPs, thus accelerating extracellular matrix degradation and metastasis in experimental models of tumorigenesis. In the present study, we focused on the role of S1P in the induction of cell invasion in a pathological condition where S1P promotes inflammation, cell proliferation and tumor aggressiveness. We show that S1P induces MMP-9 upregulation, invasive and migratory phenotypes through S1P 3 -G q coupling in human breast epithelial cells. Furthermore, we show the involvement of phospholipase C- 4 (PLC- 4 ) and Ca 2+in S1P-induced MMP-9 upregulation. Results S1P induces invasive and migratory phenotypes in MCF10A cellsTo determine the effect of S1P on invasive and migratory phenotypes of MCF10A cells, in vitro invasio...

Survival benefit of sphingosin‐1‐phosphate and receptors expressions in breast cancer patients

“…SPHK1 is an enzyme responsible for S1P production and is involved in many cellular processes, such as promoting cellular proliferation and stimulating cell survival and metastasis 2, 3, 4. SPHK1 mainly express in the cytosol and needed to be translocated to the membrane while be activated.…”

“…Sphingosine‐1‐phosphate (S1P) is a bioactive sphingolipid metabolite involved in many pathophysiological processes 1, 2, 3, 4. The intracellular level of S1P as a secondary messenger 5 is regulated by several enzymes including anabolism and catabolism.…”

ETS-1-mediated Transcriptional Up-regulation of CD44 Is Required for Sphingosine-1-phosphate Receptor Subtype 3-stimulated Chemotaxis

“…In contrast, S1P/ S1P 2 signaling was shown to stimulate Rac GTPase-activating protein (Rac-GAP) and thus abrogate growth factor-induced Rac activation and chemotaxis (25,60). S1P/S1P 3 -mediated chemotactic response was shown to play important roles in various physiological and pathophysiological responses (30,(33)(34)(35)(36)(37)(38). However, molecular details of the S1P 3 -mediated chemotactic response are poorly understood and remain to be elucidated.…”

“…However, molecular details of the S1P 3 -mediated chemotactic response are poorly understood and remain to be elucidated. S1P/S1P 3 -mediated chemotaxis was shown to play important roles in the invasion/migration phenotype of MCF10A human breast epithelial cells (33), prostate migration of carcinoma cells (30), B-cell development, egress and positioning within the bone marrow (34), homing of bone marrow-derived cells (35), dissemination of inflamed dendritic cells (36), shuttle of B cells from splenic follicular areas to marginal zone (37), and high density lipoprotein-stimulated endothelial cell migration (38), among others. We recently showed that S1P 3 receptors are abundantly expressed in a panel of human lung adenocarcinoma cell lines, and S1P 3 signaling plays an essential role in stimulating the migration/invasion of these cell lines (39).…”

Potential signaling pathway involved in sphingosine-1-phosphate-induced epithelial-mesenchymal transition in cancer

“…The S1P 2 and S1P 3 receptors could couple with the G i , G q and G 12/13 proteins to inhibit cell migration via ρ signaling (41,45). S1P modulates the levels of MMPs, such as MMP-2 and MMP-9, regulating cell invasion (46)(47)(48). Recent findings have suggested that EMT-associated MMPs are involved Figure 1.…”