Sphingosine kinase�1 promotes the metastasis of colorectal cancer by inducing the epithelial‑mesenchymal transition mediated by the FAK/AKT/MMPs axis

Liu, Shiquan; Xu, Chunyan; Wu, Wenhong; Fu, Zhenhua; He, S.; Qin, Mengbin; Huang, Jiean

doi:10.3892/ijo.2018.4607

Cited by 39 publications

(52 citation statements)

References 38 publications

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“…Constitutively active G q/11 proteins act as oncogenes [ 59 ], and thus given the role of SphK1 in cancer, it will be interesting to unravel a possible interconnection. Another important theme is the emerging role of SphK1 in epithelial–mesenchymal transition [ 60 , 61 ]; however, it should be kept in mind that besides G q/11 proteins, there are many other pathways regulating SphK1 expression and activity, and which may be important in this context. Nevertheless, we strongly believe that unravelling the mechanism(s) by which G q/11 regulates SphK1 will further help to understand the functional roles of this enzyme and facilitate its targeting by potential therapeutics.…”

Section: Resultsmentioning

confidence: 99%

Dissecting Gq/11-Mediated Plasma Membrane Translocation of Sphingosine Kinase-1

Claas

Aster

Spohner

et al. 2020

Cells

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Diverse extracellular signals induce plasma membrane translocation of sphingosine kinase-1 (SphK1), thereby enabling inside-out signaling of sphingosine-1-phosphate. We have shown before that Gq-coupled receptors and constitutively active Gαq/11 specifically induced a rapid and long-lasting SphK1 translocation, independently of canonical Gq/phospholipase C (PLC) signaling. Here, we further characterized Gq/11 regulation of SphK1. SphK1 translocation by the M3 receptor in HEK-293 cells was delayed by expression of catalytically inactive G-protein-coupled receptor kinase-2, p63Rho guanine nucleotide exchange factor (p63RhoGEF), and catalytically inactive PLCβ3, but accelerated by wild-type PLCβ3 and the PLCδ PH domain. Both wild-type SphK1 and catalytically inactive SphK1-G82D reduced M3 receptor-stimulated inositol phosphate production, suggesting competition at Gαq. Embryonic fibroblasts from Gαq/11 double-deficient mice were used to show that amino acids W263 and T257 of Gαq, which interact directly with PLCβ3 and p63RhoGEF, were important for bradykinin B2 receptor-induced SphK1 translocation. Finally, an AIXXPL motif was identified in vertebrate SphK1 (positions 100–105 in human SphK1a), which resembles the Gαq binding motif, ALXXPI, in PLCβ and p63RhoGEF. After M3 receptor stimulation, SphK1-A100E-I101E and SphK1-P104A-L105A translocated in only 25% and 56% of cells, respectively, and translocation efficiency was significantly reduced. The data suggest that both the AIXXPL motif and currently unknown consequences of PLCβ/PLCδ(PH) expression are important for regulation of SphK1 by Gq/11.

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Section: Resultsmentioning

confidence: 99%

Dissecting Gq/11-Mediated Plasma Membrane Translocation of Sphingosine Kinase-1

Claas

Aster

Spohner

et al. 2020

Cells

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“…13 As a critical mediator that connects integrin and the downstream signaling molecules, FAK can be activated by integrin phosphorylation and subsequently activates downstream PI3K/ AKT pathway and MAPK pathway. [14][15][16][17][18][19][20][21] To validate whether OSR1 exerts anti-cancer effects via FAK in COAD, we detected the activation of FAK based on p-FAK level. The results indicated that OSR1 overexpression inhibited the activation of FAK.…”

Section: Discussionmentioning

confidence: 99%

<p>Downregulation of OSR1 Promotes Colon Adenocarcinoma Progression via FAK-Mediated Akt and MAPK Signaling</p>

Zhang¹,

Jiang²

2020

OTT

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Introduction: Odd-skipped related transcription factor 1 (OSR1) is a newly identified tumor suppressor in many tumor types. However, the role and mechanism of OSR1 in colon adenocarcinoma (COAD) remain unknown. Methods: OSR1 expression was detected in COAD tissues and cells. COAD cells with OSR1 overexpression or knockdown were analyzed by in vitro CCK-8, transwell and flow cytometry assays, and by in vivo xenograft model. Results: OSR1 expression was downregulated in COAD and low expression level of OSR1 was positively correlated with tumor stage and lymph node metastasis. Furthermore, low OSR1 expression was significantly associated with poor overall survival (OS) and distant metastasis-free survival (DMFS). Lentivirus-mediated restoration of OSR1 expressioninhibited proliferation, invasion and migration while induced cell cycle arrest and apoptosis in COAD cells in vitro, and inhibited tumor growth in vivo. In contrast, OSR1 knockdown promoted proliferation, invasion and migration in COAD cells in vitro. Mechanistically, OSR1 exerted anticancer effects by inhibiting FAK-mediated activation of Akt and MAPK pathways. Conclusion: Our findings suggest that OSR1 functions as a tumor suppressor in COAD by suppressing FAK-mediated activation of Akt and MAPK pathways.

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“…Recently, sphingosine kinase (SphK) -1, an oncogenic kinase, has attracted increasing attention because of its important functions in many processes of cancer cells [12][13][14]. A few studies showed that SphK1 might mediate the EMT of A549 cells, but the mechanisms remain ambiguous [15][16].…”

Section: Introductionmentioning

confidence: 99%

SphK1 functions downstream of IGF-1 to modulate IGF-1-induced EMT, migration and paclitaxel resistance of A549 cells: A preliminary in vitro study

Wu¹,

Wu²,

Zhou³

et al. 2019

J. Cancer

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Insulin-like growth factor-1 (IGF-1)-induced epithelial-mesenchymal transition (EMT) plays a key role in the metastasis and drug resistance of non-small cell lung cancer (NSCLC). Sphingosine kinase-1 (SphK1) is also involved in EMT of NSCLC. However, the interaction between SphK1 and IGF-1 in the EMT of NSCLC is largely unknown. To clarify this issue, we examined the involvement of SphK1 in IGF-1-induced EMT using human lung cancer cell line A549, and its paclitaxel-resistant subline. Cell viability was evaluated by cell counting kit-8 assay; Migratory ability was examined using scratch wound healing test; Protein expression levels of SphK1, vimentin, fibronectin, N-cadherin and E-cadherin were detected by western blot analysis, respectively. The results showed that, IGF-1 treatment of A549 cells stimulated the expression of SphK1, the activation of ERK and AKT, the cell migration, and the expression of EMT hallmark proteins, while inhibition of SphK1 by its specific inhibitor SKI-II suppressed all the above changes and increased the sensitivity of A549 cells to paclitaxel. Our data demonstrate that SphK1 acts as a downstream effector of IGF-1 and plays a critical role in IGF-1-induced EMT, cell migration and paclitaxel resistance of A549 cells, suggesting that SphK1 might be a potential therapeutic target for NSCLC.

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Sphingosine kinase�1 promotes the metastasis of colorectal cancer by inducing the epithelial‑mesenchymal transition mediated by the FAK/AKT/MMPs axis

Cited by 39 publications

References 38 publications

Dissecting Gq/11-Mediated Plasma Membrane Translocation of Sphingosine Kinase-1

Dissecting Gq/11-Mediated Plasma Membrane Translocation of Sphingosine Kinase-1

<p>Downregulation of OSR1 Promotes Colon Adenocarcinoma Progression via FAK-Mediated Akt and MAPK Signaling</p>

SphK1 functions downstream of IGF-1 to modulate IGF-1-induced EMT, migration and paclitaxel resistance of A549 cells: A preliminary in vitro study

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