Sphingosine kinase 1 expression is regulated by signaling through PI3K, AKT2, and mTOR in human coronary artery smooth muscle cells

Francy, Jacquelyn M; Nag, Arpita; Conroy, Elizabeth J; Hengst, Jeremy A.; Yun, Jong K.

doi:10.1016/j.bbaexp.2007.03.005

Cited by 24 publications

(22 citation statements)

References 36 publications

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“…This is consistent with previous reports that AKT2, but not AKT3, is upstream of mTOR activation [53]. Based on our findings and another study [54], we propose a model of SphK1 overexpression and activation in K562 IM/R cells. In this model, overexpression of BCR-ABL activates PI3K and its downstream effectors, AKT2 and mTOR.…”

Section: Discussionsupporting

confidence: 81%

Sphingosine kinase 1 overexpression is regulated by signaling through PI3K, AKT2, and mTOR in imatinib-resistant chronic myeloid leukemia cells

Marfè

Stefano

Gambacurta

et al. 2011

Experimental Hematology

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Objective. As a better understanding of the molecular basis of carcinogenesis has emerged, oncogene-specific cell-signaling pathways have been successfully targeted to treat human malignances. Despite impressive advances in oncogene-directed therapeutics, genetic instability in cancer cells often manifest acquired resistance. This is particularly noted in the use of tyrosine kinase inhibitors therapies and not more evident than for chronic myeloid leukemia. Therefore, it is of great importance to understand the molecular mechanisms affecting cancer cell sensitivity and resistance to tyrosine kinase inhibitors. Materials and Methods. In this study, we used continuous exposure to stepwise increasing concentrations of imatinib (0.6L1 mM) to select imatinib-resistant K562 cells. Results. Expression of BCR-ABL increased both at RNA and protein levels in imatinib-resistant cell lines. Furthermore, expression levels of sphingosine kinase 1 (SphK1) were increased significantly in resistant cells, channeling sphingoid bases to the SphK1 pathway and activating sphingosine-1-phosphateLdependent tyrosine phosphorylation pathways that include the adaptor protein Crk. The partial inhibition of SphK1 activity by N,N-dimethylsphingosine or expression by small interfering RNA increased sensitivity to imatinib-induced apoptosis in resistant cells and returned BCR-ABL to baseline levels. To determine the resistance mechanism-induced SphK1 upregulation, we used pharmacological inhibitors of the phosphoinositide 3-kinase/ AKT/mammalian target of rapamycin signaling pathway and observed robust downmodulation of SphK1 expression and activity when AKT2, but not AKT1 or AKT3, was suppressed.Conclusions. These results demonstrate that SphK1 is upregulated in imatinib-resistant K562 cells by a pathway contingent on a phosphoinositide 3-kinase/AKT2/mammalian target of rapamycin signaling pathway. We propose that SphK1 plays an important role in development of acquired resistance to imatinib in chronic myeloid leukemia cell lines. Ó

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Section: Discussionsupporting

confidence: 81%

Sphingosine kinase 1 overexpression is regulated by signaling through PI3K, AKT2, and mTOR in imatinib-resistant chronic myeloid leukemia cells

Marfè

Stefano

Gambacurta

et al. 2011

Experimental Hematology

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“…As Akt2 is one of three members of Akt family that functions as the hub in the PI3K/Akt signal pathway, [37][38][39] we measured the levels of downstream p-Akt (Ser473) and p-GSK3b in NB4 and THP-1 cells after transfection with miR-29a, -29b, -29c or control mimic for 48 h and found that overexpression of each miR-29 family member downregulated the phosphorylation levels of Akt and GSK3b (Figure 3d), which was consistent with the observation that transfection of NB4 and THP-1 cells with the siRNAs that specifically probed to AKT2 decreased p-Akt and p-GSK3b levels ( Figure 3e). …”

Section: Resultsmentioning

confidence: 99%

The role, mechanism and potentially therapeutic application of microRNA-29 family in acute myeloid leukemia

et al. 2013

Cell Death Differ

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Abnormal proliferation, apoptosis repression and differentiation blockage of hematopoietic stem/progenitor cells have been characterized to be the main reasons leading to acute myeloid leukemia (AML). Previous studies showed that miR-29a and miR-29b could function as tumor suppressors in leukemogenesis. However, a comprehensive investigation of the function and mechanism of miR-29 family in AML development and their potentiality in AML therapy still need to be elucidated. Herein, we reported that the family members, miR-29a, -29b and -29c, were commonly downregulated in peripheral blood mononuclear cells and bone marrow (BM) CD34 þ cells derived from AML patients as compared with the healthy donors. Overexpression of each miR-29 member in THP1 and NB4 cells markedly inhibited cell proliferation and promoted cell apoptosis. AKT2 and CCND2 mRNAs were demonstrated to be targets of the miR-29 members, and the role of miR-29 family was attributed to the decrease of Akt2 and CCND2, two key signaling molecules. Significantly increased Akt2, CCND2 and c-Myc levels in the AML cases were detected, which were correlated with the decreased miR-29 expression in AML blasts. Furthermore, a feed-back loop comprising of c-Myc, miR-29 family and Akt2 were found in myeloid leukemogenesis. Reintroduction of each miR-29 member partially corrected abnormal cell proliferation and apoptosis repression and myeloid differentiation arrest in AML BM blasts. An intravenous injection of miR-29a, -29b and -29c in the AML model mice relieved leukemic symptoms significantly. Taken together, our finding revealed a pivotal role of miR-29 family in AML development and rescue of miR-29 family expression in AML patients could provide a new therapeutic strategy.

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“…The SKI, 2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole, which was formally named SKI-II, was developed and synthesized by our group as described previously (French et al, 2003) and was used as a specific sphingosine kinase inhibitor previously (Lee et al, 2004(Lee et al, , 2005Francy et al, 2007;Jung et al, 2007). In this article, we described SKI-II as SKI for simplicity.…”

Section: Methodsmentioning

confidence: 99%

Sphingosine 1-Phosphate Has Dual Functions in the Regulation of Endothelial Cell Permeability and Ca²⁺Metabolism

Itagaki

Yun

Hengst

et al. 2007

J Pharmacol Exp Ther

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Ca2ϩ signaling plays an important role in endothelial cell (EC) functions including the regulation of barrier integrity. Recently, the endogenous lipid derivative, sphingosine-1-phosphate (S1P), has emerged as an important modulator of EC barrier function. We investigated the role of endogenously generated S1P in Ca 2ϩ metabolism and barrier function in human umbilical endothelial cells (HUVECs) stimulated by thrombin, histamine, or other agonists. Barrier function was assessed by dextran diffusion through HUVEC monolayers, and Ca 2ϩ transients were measured using a fluoroprobe. Thrombin or histamine increased Ca 2ϩ release from the endoplasmic reticulum (ER) and Ca 2ϩ entry through store-operated channels (SOCs) that was accompanied by increased EC permeability. Inhibition of S1P synthesis by a specific sphingosine kinase inhibitor (SKI) decreased thrombin or histamine-induced increased permeability and decreased Ca 2ϩ entry via SOC in a concentrationdependent fashion. SKI had minuscule effects on thrombin or histamine-induced Ca 2ϩ release from ER. SKI also inhibited thapsigargin or ionomycin-induced Ca 2ϩ entry via SOC without affecting Ca 2ϩ release from the ER. In contrast to the effects of endogenously generated S1P, when S1P was administered externally, it initiated Ca 2ϩ release from ER similar to thrombin and histamine while decreasing EC permeability. These observations indicate that after agonist-induced conditions, endogenously generated S1P functions as a positive modulator of Ca 2ϩ entry via SOC and a mediator of increased cell permeability. In contrast, extracellular exposure to S1P has different signaling mechanisms and effects. Thus, the potential dual roles of endogenous and exogenous S1P on EC function need to be considered in pharmacological studies targeting sphingosine metabolism.

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Sphingosine kinase 1 expression is regulated by signaling through PI3K, AKT2, and mTOR in human coronary artery smooth muscle cells

Cited by 24 publications

References 36 publications

Sphingosine kinase 1 overexpression is regulated by signaling through PI3K, AKT2, and mTOR in imatinib-resistant chronic myeloid leukemia cells

Sphingosine kinase 1 overexpression is regulated by signaling through PI3K, AKT2, and mTOR in imatinib-resistant chronic myeloid leukemia cells

The role, mechanism and potentially therapeutic application of microRNA-29 family in acute myeloid leukemia

Sphingosine 1-Phosphate Has Dual Functions in the Regulation of Endothelial Cell Permeability and Ca²⁺Metabolism

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Sphingosine kinase 1 expression is regulated by signaling through PI3K, AKT2, and mTOR in human coronary artery smooth muscle cells

Cited by 24 publications

References 36 publications

Sphingosine kinase 1 overexpression is regulated by signaling through PI3K, AKT2, and mTOR in imatinib-resistant chronic myeloid leukemia cells

Sphingosine kinase 1 overexpression is regulated by signaling through PI3K, AKT2, and mTOR in imatinib-resistant chronic myeloid leukemia cells

The role, mechanism and potentially therapeutic application of microRNA-29 family in acute myeloid leukemia

Sphingosine 1-Phosphate Has Dual Functions in the Regulation of Endothelial Cell Permeability and Ca2+Metabolism

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Sphingosine 1-Phosphate Has Dual Functions in the Regulation of Endothelial Cell Permeability and Ca²⁺Metabolism