Negative regulation of cell motile and invasive activities by lysophosphatidic acid receptor-3 in colon cancer HCT116 cells

Fukui, Rui; Tanabe, Eriko; Kitayoshi, Misaho; Yoshikawa, Kyohei; Fukushima, Nobuyuki; Tsujiuchi, Toshifumi

doi:10.1007/s13277-012-0450-z

Cited by 14 publications

(11 citation statements)

References 23 publications

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“…Our results showed that LPA 1 and LPA 3 are overexpressed in HT-29 and HCT-116 cells, which are the more invasive cell lines. It was recently shown that LPA 3 expression in HCT-116 cells inhibits LPA-induced cell migration [ 16 ], suggesting that LPA 3 is a suppressor of cell motility. Likewise, we showed in this study that LPA did not induce cell migration in HT-29 and HCT-116 cells, which express high levels of LPA 3 , whereas the increased cell migration observed in Caco-2 cells could be a result of the low levels of LPA 3 ( S1 Fig [ 10 ]).…”

Section: Discussionmentioning

confidence: 99%

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LPA Induces Colon Cancer Cell Proliferation through a Cooperation between the ROCK and STAT-3 Pathways

et al. 2015

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Lysophosphatidic acid (LPA) plays a critical role in the proliferation and migration of colon cancer cells; however, the downstream signaling events underlying these processes remain poorly characterized. The aim of this study was to investigate the signaling pathways triggered by LPA to regulate the mechanisms involved in the progression of colorectal cancer (CRC). We have used three cell line models of CRC, and initially analyzed the expression profile of LPA receptors (LPAR). Then, we treated the cells with LPA and events related to their tumorigenic potential, such as migration, invasion, anchorage-independent growth, proliferation as well as apoptosis and cell cycle were evaluated. We used the Chip array technique to analyze the global gene expression profiling that occurs after LPA treatment, and we identified cell signaling pathways related to the cell cycle. The inhibition of these pathways verified the conclusions of the transcriptomic analysis. We found that the cell lines expressed LPAR1, -2 and -3 in a differential manner and that 10 μM LPA did not affect cell migration, invasion and anchorage-independent growth, but it did induce proliferation and cell cycle progression in HCT-116 cells. Although LPA in this concentration did not induce transcriptional activity of β-catenin, it promoted the activation of Rho and STAT-3. Moreover, ROCK and STAT-3 inhibitors prevented LPA-induced proliferation, but ROCK inhibition did not prevent STAT-3 activation. Finally, we observed that LPA regulates the expression of genes related to the cell cycle and that the combined inhibition of ROCK and STAT-3 prevented cell cycle progression and increased the LPA-induced expression of cyclins E1, A2 and B1 to a greater degree than either inhibitor alone. Overall, these results demonstrate that LPA increases the proliferative potential of colon adenocarcinoma HCT-116 cells through a mechanism involving cooperation between the Rho-ROCK and STAT3 pathways involved in cell cycle control.

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Section: Discussionmentioning

confidence: 99%

“…Additionally, it was shown that LPA 1 mediates the LPA-stimulated cell scattering of DLD-1 cells using a shRNA-lentivirus system [ 15 ]. Moreover, LPA 3 knockdown increases the migration and invasion of HCT-116 cells [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

LPA Induces Colon Cancer Cell Proliferation through a Cooperation between the ROCK and STAT-3 Pathways

et al. 2015

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“…Studies in other cells have yielded varying results. LPAR3 has been implicated in ovarian cancer progression and cell migration [45,46], but was also reported to inhibit cell migration and invasion in colon cancer cells [47]. LPAR1 has been found to induce migration in cells from breast cancer [48], pancreatic cancer [49], and hepatocellular carcinoma [50] while it inhibited metastasis and invasion in prostate organotypic models [51].…”

Section: Discussionmentioning

confidence: 99%

Role of LPAR3, PKC and EGFR in LPA-induced cell migration in oral squamous carcinoma cells

et al. 2014

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BackgroundOral squamous cell carcinoma is an aggressive neoplasm with serious morbidity and mortality, which typically spreads through local invasive growth. Lysophosphatidic acid (LPA) is involved in a number of biological processes, and may have a role in cancer cell migration and invasiveness. LPA is present in most tissues and can activate cells through six different LPA receptors (LPAR1-6). Although LPA is predominantly promigratory, some of the receptors may have antimigratory effects in certain cells. The signalling mechanisms of LPA are not fully understood, and in oral carcinoma cells the specific receptors and pathways involved in LPA-stimulated migration are unknown.MethodsThe oral carcinoma cell lines E10, SCC-9, and D2 were investigated. Cell migration was studied in a scratch wound assay, and invasion was demonstrated in organotypic three dimensional co-cultures. Protein and mRNA expression of LPA receptors was studied with Western blotting and qRT-PCR. Activation of signalling proteins was examined with Western blotting and isoelectric focusing, and signalling mechanisms were further explored using pharmacological agents and siRNA directed at specific receptors and pathways.ResultsLPA stimulated cell migration in the two oral carcinoma cell lines E10 and SCC-9, but was slightly inhibitory in D2. The receptor expression profile and the effects of specific pharmacological antagonist and agonists indicated that LPA-stimulated cell migration was mediated through LPAR3 in E10 and SCC-9. Furthermore, in both these cell lines, the stimulation by LPA was dependent on PKC activity. However, while LPA induced transactivation of EGFR and the stimulated migration was blocked by EGFR inhibitors in E10 cells, LPA did not induce EGFR transactivation in SCC-9 cells. In D2 cells, LPA induced EGFR transactivation, but this was associated with slowing of a very high inherent migration rate in these cells.ConclusionThe results demonstrate LPA-stimulated migration in oral carcinoma cells through LPAR3, mediated further by PKC, which acts either in concert with or independently of EGFR transactivation.

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“…Collectively, these data mean that the ATX/LPC/LPA pathway is inhibitory for recruitment of the granulocyte in this experimental model in vivo. Although the chemoattractive effects of LPA on human neutrophil [18,19] and monocytic cell lines in vitro [20] have been reported to be positive, increasing evidence shows negative regulation of cell motility by LPA in cancerous cells that is dependent on a combination of receptor subtypes and cell types [13,[21][22][23]. The negative chemoattractive effect of the ATX/LPA pathway in regressing CL is further supported by the spatial dissociation of ATX and LPA 4 localization and by a negative correlation between increased ATX expression and decreased phagocyte number during the resolution of inflammation (stages 3 and 4).…”

Section: Discussionmentioning

confidence: 99%

Autotaxin as a novel, tissue-remodeling-related factor in regressing corpora lutea of cycling rats

Masuda

Haruta

Orino

et al. 2013

FEBS J

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Autotaxin (ATX) generates lysophosphatidic acid (LPA) from glycerophospholipid via lysophospholipase D (lysoPLD) activity in cooperation with phospholipase A. We studied its expression and possible functional roles in the ovary of nonfertile cycling rats. Immunohistochemistry revealed that ATX was located predominantly in luteal steroidogenic cells of corpora lutea (CL), but not in any follicles. ATX expression was modest in the newest generation of CL and augmented in older generations undergoing structural regression. ATX expression in the whole ovary and lysoPLD activity in circulating blood did not alter during the estrous cycle. Among the LPA receptors examined (LPA 1-4 ), LPA 4 was densely present on migratory cells, probably phagocytes, at degenerative foci within regressing CL. Bolus administration of anti-ATX IgG or LPA into ovarian bursa in vivo had little effect on the apoptotic cell death of luteal cells, as evaluated by cleaved caspase 3 expression, but led to altered numbers of neutrophils and macrophages in regressing CL, as evaluated by immunological detection of each cell marker. These treatments, together with bromodeoxy uridine, revealed a stimulatory effect of the ATX/LPA pathway on fibroblast proliferation in regressing CL. The results indicate that ATX is increasingly expressed by structurally regressing CL and has definite local action on phagocyte recruitment and fibroblast proliferation which are responsible for tissue remodeling.

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Negative regulation of cell motile and invasive activities by lysophosphatidic acid receptor-3 in colon cancer HCT116 cells

Cited by 14 publications

References 23 publications

LPA Induces Colon Cancer Cell Proliferation through a Cooperation between the ROCK and STAT-3 Pathways

LPA Induces Colon Cancer Cell Proliferation through a Cooperation between the ROCK and STAT-3 Pathways

Role of LPAR3, PKC and EGFR in LPA-induced cell migration in oral squamous carcinoma cells

Autotaxin as a novel, tissue-remodeling-related factor in regressing corpora lutea of cycling rats

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