The ins and outs of lysophosphatidic acid signaling

Moolenaar, Wouter H.; Meeteren, Laurens A. van; Giepmans, Ben N. G.

doi:10.1002/bies.20081

Cited by 525 publications

(507 citation statements)

References 89 publications

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“…Further downstream is Rac, a small GTP binding protein of the Rho family. Rac is a downstream affector in GPCR pathways that has been shown to be regulated by S1P [14] and LPA [15] and is known to induce cell motility via urokinase plasminogen activator (uPA) receptor induced actin cytoskeletal changes [16] and the loss of stress fibers as result of Rho inactivation [17].…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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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“…It has also been observed that ovarian tumors synthesize and secrete LPA, thereby increasing LPA levels in the ascitic fluid and serum of ovarian cancer patients (Xu et al, 1995;Andre et al, 2002). Furthermore, the growth factor like activity of LPA in stimulating cancer cell proliferation, migration, and invasiveness has been well documented (Moolenaar et al, 2004). Considering the importance of such LPA and LPAR-mediated autocrine and paracrine signaling pathways in tumor etiology and progression, there has been a major focus in identifying the G protein that couples LPARs to cell proliferation (Anliker and Chun, 2004).…”

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confidence: 98%

Mitogenic signaling by lysophosphatidic acid (LPA) involves Gα12

Radhika

Jayaraman

et al. 2005

Oncogene

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Lysophosphatidic acid (LPA), a major G protein coupled receptor (GPCR)-activating ligand present in serum, elicits growth factor like responses by stimulating specific GPCRs coupled to heterotrimeric G proteins such as G i , G q , and G 12/13 . Previous studies have shown that the overexpression of wild-type Ga 12 (Ga 12 WT) results in the oncogenic transformation of NIH3T3 cells (Ga 12 WT-NIH3T3) in a serum-dependent manner. Based on the potent growth-stimulating activity of LPA and the presence of LPA and LPA-like molecules in the serum, we hypothesized that the serum-dependent neoplastic transformation of Ga 12 WT-NIH3T3 cells was mediated by the stimulation of LPA-receptors (LPARs) by LPA in the serum. In the present study, using guanine nucleotide exchange assay and GST-TPR binding assay, we show that the treatment of Ga 12 WT-NIH3T3 with 2 lM LPA leads to the activation of Ga 12 . Stimulation of these cells with LPA promotes JNK-activation, a critical component of Ga 12 -response and cell proliferation. We also show that LPA can substitute for serum in stimulating JNK-activity, DNA synthesis, and proliferation of Ga 12 WT-NIH3T3 cells. LPA-mediated proliferative response in NIH3T3 cells involves Ga 12 , but not the closely related Ga 13 . Pretreatment of Ga 12 WT-NIH3T3 cells with suramin (100 lM), a receptor-uncoupling agent, inhibited LPAstimulated proliferation of these cells by 55% demonstrating the signal coupling between cell surface LPAR and Ga 12 in the neoplastic proliferation of NIH3T3 cells. As LPA and LPAR mediated mitogenic pathways have been shown to play a major role in tumor genesis and progression, a mechanistic understanding of the signal coupling between LPAR, Ga 12 , and the downstream effectors is likely to unravel additional targets for novel cancer chemotherapies.

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“…LPA is a phospholipid that is known to produce various cellular responses via stimulation of G protein families such as Gi, G12, and Gq [17][18][19] . Subsequent to the finding of high expression in ovarian cancer patients, LPA has been reported to be involved in processes in various cells that have an important effect on the development of cancer, such as proliferation, migration, and survival 20) .…”

Section: Discussionmentioning

confidence: 99%

Lysophosphatidic Acid-Induced TWIST1 and Slug Expression in Oral Cancer Cell Invasion

Cho

2017

J Dent Hyg Sci

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Relative to its incidence, oral cancer has serious negative social effects. The exact causes of oral cancer have not been clarified, but many studies have implicated smoking and drinking. However, the fundamental mechanism of oral cancer causation has yet to be elucidated. Lysophosphatidic acid (LPA) augments epithelial mesenchymal transition (EMT) and development of various cancer cells. However, a detailed mechanistic explanation for LPA-induced EMT and the effects of EMT-promoting conditions on oral squamous cell carcinoma development remain elusive. In the present study, a quantitative reverse transcription polymerase chain reaction was used to analyze TWIST1, Slug, E-cadherin, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) transcript expression. Immunoblotting was used to analyze TWIST1, Slug, E-cadherin, and GAPDH protein expression. siRNAs were used to silence TWIST1 and Slug transcript expression. A matrigel-coated in vitro invasion insert was used to analyze oral cancer cell invasion. The results of the present study show that the expression levels of TWIST1 and Slug, which are EMT factors, were increased by LPA treatment in YD-10B oral squamous cell carcinoma. Conversely, E-cadherin expression was significantly reduced. In addition, transfection of the cells with TWIST1 and Slug siRNA strongly inhibited LPA-induced oral cancer cell invasion. The present study shows that TWIST1 and Slug mediate LPA-induced oral cancer cell EMT and invasiveness. The present study confirmed the mechanism by which LPA promotes oral cancer cell development, with TWIST1 and Slug providing novel biomarkers and promising therapeutic targets for oral cancer cell development.

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The ins and outs of lysophosphatidic acid signaling

Cited by 525 publications

References 89 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

Mitogenic signaling by lysophosphatidic acid (LPA) involves Gα12

Lysophosphatidic Acid-Induced TWIST1 and Slug Expression in Oral Cancer Cell Invasion

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