Cancer cell-derived 12(S)-HETE signals via 12-HETE receptor, RHO, ROCK and MLC2 to induce lymph endothelial barrier breaching

Nguyen, Chi Huu; Stadler, Serena; Brenner, Stefan; Huttary, Nicole; Krieger, Sigurd; Jäger, Walter; Dolznig, Helmut; Krupitza, Georg

doi:10.1038/bjc.2016.201

Cited by 31 publications

(22 citation statements)

References 26 publications

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“…As 12(S)-HETE causes the retraction of LECs (4), whether SOX18 and BLT2 also contribute to this phenomenon was investigated. LEC retraction was measured in a validated in vitro co-culture assay calculating the areas of generated CCIDs in LEC monolayers underneath 12(S)-HETE-secreting MDA-MB231 cell spheroids (4,32). The CCID areas that were triggered by MDA-MB213 spheroids were significantly smaller in those LEC monolayers, which were transfected with siRNAs targeting SOX18 or BLT2 ( Fig.…”

Section: (S)-hete Induces Sox18mentioning

confidence: 99%

12(S)-HETE induces lymph endothelial cell retraction inï¿½vitro by upregulation of SOX18

et al. 2018

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Metastasising breast cancer cells communicate with adjacent lymph endothelia, intravasate and disseminate through lymphatic routes, colonise lymph nodes and finally metastasize to distant organs. Thus, understanding and blocking intravasation may attenuate the metastatic cascade at an early step. As a trigger factor, which causes the retraction of lymph endothelial cells (LECs) and opens entry ports for tumour cell intravasation, MDA-MB231 breast cancer cells secrete the pro-metastatic arachidonic acid metabolite, 12S-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid [12(S)-HETE]. In the current study, treatment of LECs with 12(S)-HETE upregulated the expression of the transcription factors SRY-related HMG-box 18 (SOX18) and prospero homeobox protein 1 (PROX1), which determine endothelial development. Thus, whether they have a role in LEC retraction was determined using a validated intravasation assay, small interfering RNA mediated knockdown of gene expression, and mRNA and protein expression analyses. Specific inhibition of SOX18 or PROX1 significantly attenuated in vitro intravasation of MDA-MB231 spheroids through the LEC barrier and 12(S)-HETE-triggered signals were transduced by the high and low affinity receptors, 12(S)-HETE receptor and leukotriene B4 receptor 2. In addition, the current findings indicate that there is crosstalk between SOX18 and nuclear factor κ-light-chain-enhancer of activated B cells, which was demonstrated to contribute to MDA-MB231/lymph endothelial intravasation. The present data demonstrate that the endothelial-specific and lymph endothelial-specific transcription factors SOX18 and PROX1 contribute to LEC retraction.

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Section: (S)-hete Induces Sox18mentioning

confidence: 99%

12(S)-HETE induces lymph endothelial cell retraction inï¿½vitro by upregulation of SOX18

et al. 2018

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“…This finding is consistent with previous reports demonstrating that the 12-LOXderived oxylipin of AA, 12-HETE, binds the orphan GPCR GPR31 in cancer cells. [10][11][12] GPR31 has not yet been shown to be expressed on platelets, and on the basis of the data presented here (Figure 1), it is Dunn's multiple comparison post-test was performed comparing DMSO with each condition. *P , .05, **P , .01, ***P , .001.…”

Section: Org Frommentioning

confidence: 99%

12-HETrE inhibits platelet reactivity and thrombosis in part through the prostacyclin receptor

et al. 2017

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Key Points• The antiplatelet effects of 12-HETrE in humans and mice are partly dependent on IP in vitro.• The antithrombotic effects of 12-HETrE are partially dependent on IP in vivo in mice.The dihomo-g-linolenic acid (DGLA)-derived metabolite of 12-lipoxygenase, 12-hydroxyeicosatrienoic acid (12-HETrE), was recently shown to potently inhibit thrombus formation without prolonging bleeding in murine models. Although 12-HETrE was found to inhibit platelet activation via the Ga s signaling pathway, the Ga s -coupled receptor by which 12-HETrE mediates its antiplatelet effects has yet to be identified. Defining the receptor by which 12-HETrE exerts its effects is key to determining its therapeutic potential as an antiplatelet drug. Therefore, the goal of this study was to determine the Ga s -coupled platelet receptor through which 12-HETrE exerts its antiplatelet effects. In this study, we showed that pharmacological inhibition of the prostacyclin (IP) receptor in human platelets or genetic ablation of IP in murine platelets prevented 12-HETrE from blocking aggregation in vitro.Furthermore, the antithrombotic effects of 12-HETrE were significantly diminished in IP knockout mice in vivo. Together these data demonstrate that the antiplatelet effects of 12-HETrE are at least partially dependent on IP signaling. Importantly, this work identified 12-HETrE as a novel regulator of IP signaling that may aid in the rationale for design of novel therapeutics to inhibit platelet function. Additionally, this study provides further insight into the mechanism by which DGLA supplementation inhibits platelets function.

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“…As a proinflammatory lipid mediator, 12(S)-HETE has been shown to promote vasodilation (Faraci et al, 2001) and promote cell-derived microvesicle internalization in PMNLs (Duchez et al, 2015). In addition, 12(S)-HETE actively participates in several types of inflammatory diseases including cancer (Ding et al, 2001;Nguyen et al, 2016), atherosclerosis (Cyrus et al, 1999), and arthritis (Duchez et al, 2015). Among the compounds that have generated interest in the field of eicosanoid regulation, which includes 12(S)-HETE, are the naturally occurring polyphenols including the flavonoids, a class of bioactive plant compounds that exhibits several beneficial properties (Werz, 2007;Boudreau et al, 2012Boudreau et al, , 2017Macready et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Identification of Peracetylated Quercetin as a Selective 12-Lipoxygenase Pathway Inhibitor in Human Platelets

et al. 2018

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The inflammatory response is necessary for the host's defense against pathogens; however, uncontrolled or unregulated production of eicosanoids has been associated with several types of chronic inflammatory diseases. Thus, it is not surprising that enzymes implicated in the production of eicosanoids have been strategically targeted for potential therapeutic approaches. The 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] lipid mediator is among inflammatory molecules that are abundantly produced in various diseases and is primarily biosynthesized via the 12(S)lipoxygenase pathway. The effects of the abundance of 12(S)-HETE and its contribution to several chronic inflammatory diseases have been well studied over the last few years. While most developed compounds primarily target the 5-lipoxygenase (5-LO) or the cyclooxygenase (COX) pathways, very few compounds selectively inhibiting the 12-lipoxygenase (12-LO) pathway are known. In this study, we examined whether the distribution of hydroxyl groups among flavones could influence their potency as 12-LO inhibitors. Using human platelets, the human embryonic kidney 293 (HEK293) cell line expressing 5-LO, and human polymorphonuclear leukocytes (PMNLs) we investigated the effects of these compounds on several inflammatory pathways, namely, 12-LO, 5-LO, and COX. Using high-resolution respirometry and flow cytometry, we also evaluated some normal cell functions that could be modulated by our compounds. We identified a peracetylated quercetin (compound 6) that exerts potent inhibitory activity toward the platelet 12-LO pathway (IC 50 5 1.53 mM) while having a lesser affinity toward the COX pathway. This study characterizes the peracetylated quercetin (compound 6) as a more selective platelet-type 12-LO inhibitor than baicalein, with no measurable nontargeted effects on the platelet's activation or overall cell's oxygen consumption.

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Cancer cell-derived 12(S)-HETE signals via 12-HETE receptor, RHO, ROCK and MLC2 to induce lymph endothelial barrier breaching

Cited by 31 publications

References 26 publications

12(S)-HETE induces lymph endothelial cell retraction inï¿½vitro by upregulation of SOX18

12(S)-HETE induces lymph endothelial cell retraction inï¿½vitro by upregulation of SOX18

12-HETrE inhibits platelet reactivity and thrombosis in part through the prostacyclin receptor

Identification of Peracetylated Quercetin as a Selective 12-Lipoxygenase Pathway Inhibitor in Human Platelets

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