Lysophosphatidic acid (LPA) effects on endometrial carcinoma in vitro proliferation, invasion, and matrix metalloproteinase activity

Wang, Fengqiang; Ariztia, Edgardo V.; Boyd, Leslie R.; Horton, Faith R.; Smicun, Yoel; Hetherington, Jessica A.; Smith, Philip; Fishman, David A.

doi:10.1016/j.ygyno.2009.12.012

Cited by 23 publications

(18 citation statements)

References 59 publications

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“…None of the previous studies (in monolayer culture) reporting migration-promoting effects of LPA/S1P were based on organotypic, multicellular structures, and unable to track invasion of cell aggregates into the ECM. Additional studies rely on invasion models that monitor chemotactic motility of single cells, for example, Boyden chamber (Hope et al , 2009; Wang et al , 2010), or scratch/wound-healing assays (Fishman et al , 2001; Vogler et al , 2003; Wang et al , 2010). Our experimental settings focus instead on the plasticity of multicellular epithelial structures including the BM and dynamic turnover of cell-matrix contacts.…”

Section: Discussionmentioning

confidence: 99%

Lysophosphatidic acid and sphingosine-1-phosphate promote morphogenesis and block invasion of prostate cancer cells in three-dimensional organotypic models

et al. 2011

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Normal prostate and some malignant prostate cancer (PrCa) cell lines undergo acinar differentiation and form spheroids in three-dimensional (3-D) organotypic culture. Acini formed by PC-3 and PC-3M, less pronounced also in other PrCa cell lines, spontaneously undergo an invasive switch, leading to the disintegration of epithelial structures and the basal lamina, and formation of invadopodia. This demonstrates the highly dynamic nature of epithelial plasticity, balancing epithelial-to-mesenchymal transition against metastable acinar differentiation. This study assessed the role of lipid metabolites on epithelial maturation. PC-3 cells completely failed to form acinar structures in delipidated serum. Adding back lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) rescued acinar morphogenesis and repressed invasion effectively. Blocking LPA receptor 1 (LPAR1) functions by siRNA (small interference RNA) or the specific LPAR1 inhibitor Ki16425 promoted invasion, while silencing of other G-protein-coupled receptors responsive to LPA or S1P mainly caused growth arrest or had no effects. The G-proteins Gα12/13 and Gαi were identified as key mediators of LPA signalling via stimulation of RhoA and Rho kinases ROCK1 and 2, activating Rac1, while inhibition of adenylate cyclase and accumulation of cAMP may be secondary. Interfering with these pathways specifically impeded epithelial polarization in transformed cells. In contrast, blocking the same pathways in non-transformed, normal cells promoted differentiation. We conclude that LPA and LPAR1 effectively promote epithelial maturation and block invasion of PrCa cells in 3-D culture. The analysis of clinical transcriptome data confirmed reduced expression of LPAR1 in a subset of PrCa's. Our study demonstrates a metastasis-suppressor function for LPAR1 and Gα12/13 signalling, regulating cell motility and invasion versus epithelial maturation.

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Section: Discussionmentioning

confidence: 99%

Lysophosphatidic acid and sphingosine-1-phosphate promote morphogenesis and block invasion of prostate cancer cells in three-dimensional organotypic models

et al. 2011

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“…For proliferation assays, cells were grown in 24-well plates and incubated with 0.5 μCi [ 3 H]-thymidine/ml (Perkin Elmer) for the last 4 hours of treatment, lysed, and radioactivity incorporated into cellular DNA counted in a liquid scintillation counter. For viability assays, the CellTiter 96® AQueous One Solution (MTS) reagent was used following the manufacturer's protocol (Promega) as previously described (24). Cellular ATP levels were assessed by using an ATP assay kit (Calbiochem) as previously described (25).…”

Section: Methodsmentioning

confidence: 99%

Metformin Prevents the Development of Oral Squamous Cell Carcinomas from Carcinogen-Induced Premalignant Lesions

Vitale‐Cross

Molinolo

Martin

et al. 2012

Cancer Prevention Research

129

123

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Head and neck squamous cell carcinoma (HNSCC) is a major public health concern. The recent identification of the mammalian Target of Rapamycin Complex 1 (mTORC1) signaling pathway as a highly prevalent molecular signature underlying HNSCC pathogenesis has provided the foundation to search for novel therapeutic approaches to prevent and treat HNSCC. Here, we asked whether metformin, the most widely used medication for the treatment of type 2 diabetes, which acts in part by stimulating the AMP-activated protein kinase (AMPK) signaling pathway thereby reducing mTORC1 activity, may lower the risk of HNSCC development. Indeed, we show that metformin reduces the growth of HNSCC cells and diminishes their mTORC1 activity by both AMPK-dependent and –independent mechanisms. We also optimized an oral-specific carcinogenesis mouse model that results in the accumulation of multiple oral premalignant lesions at the end of the carcinogen exposure, some of which then spontaneously progress into HNSCC. Using this mouse model, we observed that metformin specifically inhibits mTORC1 in the basal proliferating epithelial layer of oral premalignant lesions. Remarkably, metformin prevented the development of HNSCC by reducing significantly the size and number of carcinogen-induced oral tumoral lesions, and by preventing their spontaneous conversion to squamous cell carcinomas. Collectively, our data underscore the potential clinical benefits of using metformin as a targeted chemopreventive agent in the control of HNSCC development and progression.

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“…Lysophosphatidic acid (LPA), also known as an important lipid mediator, is a potent regulator of proliferation and migration in many cell lines (Van Meeteren and Moolenaar,2007; Pua et al,2009; Liu et al,2010; Wang et al,2010). Extracellular LPA is thought to be produced primarily by the autotaxin (ATX)/lysophospholipase D (lysoPLD) pathway.…”

Section: Introductionmentioning

confidence: 99%

ATX–LPA Axis Induces Expression of OPN in Hepatic Cancer Cell SMMC7721

Zhang

Pan

Huang

et al. 2010

The Anatomical Record

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Osteopontin (OPN) and autotaxin (ATX) are important chemokines involved in the survival, proliferation, migration, invasion, and metastasis of many cancer cells. The focus of the study was to investigate the relationship between OPN and ATX-lysophosphatidic acid (LPA) axis. The expression of OPN and its cellular cascades were determined by western blot and real-time quantitative transcription polymerase chain reaction (real-time PCR) analyses. Cell migration activity was determined by a Transwell-migration assay. In comparison with nontreated cells, we found that the ATX-LPA axis upregulated OPN expression by 2.91-fold in protein levels and 2.52-fold in mRNA levels. The ATX-LPA axis activates Akt and ATX/LPC-induced OPN expression in SMMC7721 cells was largely reduced by the inhibitors of phosphatidylinositol 3-kinase (PI3K)/ Akt or LPA receptor. This study provides the first evidence that the induction of the OPN expression by ATX-LPA axis was mediated by the activation of Akt through LPA receptors and OPN was required for migration of SMMC7721 cells induced by ATX-LPA axis. Anat Rec, 294:406-411, 2011. V V C 2010 Wiley-Liss, Inc.

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Lysophosphatidic acid (LPA) effects on endometrial carcinoma in vitro proliferation, invasion, and matrix metalloproteinase activity

Cited by 23 publications

References 59 publications

Lysophosphatidic acid and sphingosine-1-phosphate promote morphogenesis and block invasion of prostate cancer cells in three-dimensional organotypic models

Lysophosphatidic acid and sphingosine-1-phosphate promote morphogenesis and block invasion of prostate cancer cells in three-dimensional organotypic models

Metformin Prevents the Development of Oral Squamous Cell Carcinomas from Carcinogen-Induced Premalignant Lesions

ATX–LPA Axis Induces Expression of OPN in Hepatic Cancer Cell SMMC7721

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