Sphingosine Kinases and Sphingosine-1-Phosphate Are Critical for Transforming Growth Factor β-Induced Extracellular Signal-Regulated Kinase 1 and 2 Activation and Promotion of Migration and Invasion of Esophageal Cancer Cells

Miller, Anna V.; Alvarez, Sergio E.; Spiegel, Sarah; Lebman, Deborah A.

doi:10.1128/mcb.01465-07

Cited by 78 publications

(69 citation statements)

References 52 publications

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“…We confirmed that Lith-O-Asp treatment decreased a-2,6-and a-2,3-sialylation of integrin-(1; decreased p-FAK(Y31), p-paxillin(Y397), MMP2, MMP9 protein expression; and decreased Rho activity ( (Table 1). For example, CCT6A, which is a chaperonin and stimulates TGF-b-mediated migration and invasion through maturation of sphingosine kinases 1 (34), and WDR1, which is essential for actin dynamics through interaction with cofilin (35), showed decreased expression after Lith-O-Asp treatment. Interestingly, we observed an increase in p-cofilin (Fig.…”

Section: Discussionmentioning

confidence: 99%

A Novel Sialyltransferase Inhibitor Suppresses FAK/Paxillin Signaling and Cancer Angiogenesis and Metastasis Pathways

et al. 2011

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Increased sialyltransferase (ST) activity promotes cancer cell metastasis, and overexpression of cell surface sialic acid correlates with poor prognosis in cancer patients. To seek therapies targeting metastasis for cancer treatment, we developed a novel ST inhibitor, Lith-O-Asp, and investigated its antimetastatic and antiangiogenic effects and mechanisms. We found that cells treated with Lith-O-Asp showed a reduction of activity on various ST enzymes by in vitro and cell-based activity analyses. Lith-O-Asp inhibited migration and invasion abilities in various cancer cell lines and showed inhibitory effect on the angiogenic activity of human umbilical vein endothelial cells. Indeed, Lith-O-Asp treatment consequently delayed cancer cell metastasis in experimental and spontaneous metastasis assays in animal models. Importantly, Lith-O-Asp decreased the sialic acid modification of integrin-b1 and inhibited the expression of phospho-FAK, phospho-paxillin, and the matrix metalloprotease

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Section: Discussionmentioning

confidence: 99%

A Novel Sialyltransferase Inhibitor Suppresses FAK/Paxillin Signaling and Cancer Angiogenesis and Metastasis Pathways

et al. 2011

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“…It was reported that S1P/S1PR1 signaling is indispensable for TGF-␤ signaling in EMT. 33 Thus, it would be interesting to investigate the effect of TGF-␤ signaling in S1PR1-deficient embryos in future.…”

Section: Requirements Of Smad2/3for Vascular Stability 5325mentioning

confidence: 99%

Smad2/Smad3 in endothelium is indispensable for vascular stability via S1PR1 and N-cadherin expressions

Itoh

Adachi

et al. 2012

Blood

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Transforming growth factor-␤ (TGF-␤) is involved in vascular formation through activin receptor-like kinase (ALK)1 and ALK5. ALK5, which is expressed ubiquitously, phosphorylates Smad2 and Smad3, whereas endothelial cell (EC)-specific ALK1 activates Smad1 and Smad5. Because ALK5 kinase activity is required for ALK1 to transduce TGF-␤ signaling via Smad1/5 in ECs, ALK5 knockout (KO) mice were not able to give us the precise mechanisms by which TGF-␤/ALK5/Smad2/3 signaling is implicated in angiogenesis. To delineate the role of Smad2/3 signaling in endothelium, the Smad2 gene in Smad3 KO mice was selectively deleted in ECs using Tie2-Cre transgenic mice, termed EC-specific Smad2/3 double KO (EC-Smad2/3KO) mice. EC-Smad2/3KO embryos revealed hemorrhage leading to embryonic lethality around E12.5. EC-Smad2/3KO embryos exhibited no abnormality of vasculogenesis and angiogenesis in both the yolk sac and the whole embryo, whereas vascular maturation was incomplete because of inadequate assembly of mural cells in the vasculature. Wide gaps between ECs and mural cells could be observed in the vasculature of EC-Smad2/3KO mice because of reduced expression of Ncadherin and sphingosine-1-phosphate receptor-1 (S1PR1) in ECs from those mice. These results indicated that Smad2/3 signaling in ECs is indispensable for maintenance of vascular integrity via the fine-tuning of N-cadherin, VEcadherin, and S1PR1 expressions in the vasculature.(Blood. 2012;119(22): 5320-5328) IntroductionAberrant vascularization leads to a number of diseases including atherosclerosis, tumorigenicity, and retinopathy, 1,2 whereas angiogenesis is essential during embryonic development as well as in adulthood. Angiogenesis is mediated by sprouting of new vessels from preexisting ones or by intussusceptive microvascular growth. In general, vascular formation is quiet in adulthood, although angiogenesis involved in wound healing, inflammation, ischemia, and the female reproductive cycle can be observed. Angiogenesis is divided into 2 phases: the activation phase and the resolution phase. The balance between physiologic stimulators (eg, vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF-2), angiopoietins, and hypoxia) and inhibitors (eg, angiostatin, endostatin, and interferon-␣) is strategic to tuning of the angiogenic switch. Proliferation of endothelial cells (ECs), increase in vascular permeability, and degradation of extracellular matrix components can be observed during the activation phase. Consequently, ECs make new capillary sprouts. In the resolution phase, the proliferation and migration of ECs ceases and is followed by reconstitution of the basement membrane and maturation of the vessels. 3 Transforming growth factor-␤ (TGF-␤) is a pivotal cytokine that contributes to the behaviors and activities of most cells from the embryonic to the adult stage. The TGF-␤ signal is initiated when the ligand binds to its own TGF-␤ type II receptor (T␤RII); thereafter, the TGF-␤ type I receptor (T␤RI or activin receptor-like kinase [ALK]...

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“…45 Moreover, transforming growth factor-␤-induced migration and invasion of esophageal cancer cells was shown to involve SK-1-generated S1P via S1P2 signaling. 46 It should be noted, however, that disruption of the S1P2 gene led to the development of diffuse large B-cell lymphoma (DLBCL) in approximately half of S1P2 Ϫ/Ϫ KO mice within 1.5 to 2 years of age. 47 Thus, long-term targeting of S1P2 might have some unwanted consequences.…”

mentioning

confidence: 99%

Sphingosine kinase-1 and sphingosine 1-phosphate receptor 2 mediate Bcr-Abl1 stability and drug resistance by modulation of protein phosphatase 2A

Salas

Ponnusamy

Senkal

et al. 2011

Blood

104

106

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Introduction CML is a clonal disorder of pluripotent hematopoietic stem cells characterized by the Philadelphia (Ph) chromosome, which results from the reciprocal translocation between the long arms of chromosomes 9 and 22. 1-4 This hybrid B-cell receptor (BCR)-ABL1 gene encodes for a fusion protein Bcr-Abl1 with a constitutive tyrosine kinase activity. 3,4 Despite high rates of clinical responses in early chronic phase CML (CML-CP) to the Bcr-Abl1 kinase inhibitor imatinib, 5-8 development of resistance is a major problem in late CML-CP and in the treatment of blast crisis CML (CML-BC). 9-12 Although Bcr-Abl1-independent mechanisms also exist, 13-15 resistance in CML-CP is usually associated with the expression of mutant Bcr-Abl1 proteins, including T315I and Y253F/H mutations against which the second generation ABL tyrosine kinase inhibitors (TKI) such as nilotinib and/or dasatinib show limited effect. 15-17 Nonetheless , BCR-ABL1 mutations may not account for all cases of drug resistance in CML (CP and BC); indeed, alternative Bcr-Abl1-dependent mechanisms including alterations of sphingolipid metabolism and signaling, 18 might account for TKI resistance. Sphingolipids, ceramide and sphingosine 1-phosphate (S1P) included, are a family of membrane lipids with important roles in the regulation of the fluidity and subdomain structure of membranes. 19-21 Ceramide can be hydrolyzed by ceramidases to release sphingosine, which is phosphorylated by sphingosine kinases-1 or-2 (SK-1 or SK-2) to generate S1P. 20 Ceramide plays proapoptotic roles 21 whereas S1P mediates proliferation and/or resistance to apoptosis 22,23 generally via G-protein-coupled S1P1-5 receptor signaling. 24 However, receptor-independent intracellular functions of S1P were also reported. 25 Recently, alteration of the balance between the proapoptotic ceramide and antiapoptotic S1P via up-regulation of SK-1 was shown to mediate imatinib resistance in K562 CML-BC patient-derived cells by an unknown mechanism. 18 Here, we report the identification of a novel mechanism by which SK-1/S1P mediates imatinib resistance by regulation of the PP2A-dependent and SHP-1-mediated Bcr-Abl1 dephosphoryla-tion and stability selectively via receptor 2 (S1P2) signaling in CML (CP and BC). In addition, our data suggest that targeting the SK-1/S1P2 signaling axis provides a novel strategy to modulate wild-type (wt) or mutant (T315I or Y253H) Bcr-Abl1 stability by restoring PP2A function, and attenuate drug resistance both in cell culture and in mice bearing 32D/T315I-Bcr-Abl1 allografts. Human CML cell lines K562, LAMA4, and their imatinib-resistant derivatives K562/IMA-0.1,-1,-3, or LAMA4/IMA, were maintained as described. 18 The Bcr-Abl-expressing 32Dcl3 cells, 32D-p210 Bcr-Abl (wt), 32D-p210 Bcr-Abl (Y253H) and (T315I) were maintained in RPMI containing 15% FBS, 2mM L-glutamine, and penicillin and streptomycin (P/S; 100 ng/mL each). MEFs (wt and SK-1 /) were maintained in DMEM with 10% FBS and P/S. Human CD34 primary cells from CML patients and normal donor were obt...

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Sphingosine Kinases and Sphingosine-1-Phosphate Are Critical for Transforming Growth Factor β-Induced Extracellular Signal-Regulated Kinase 1 and 2 Activation and Promotion of Migration and Invasion of Esophageal Cancer Cells

Cited by 78 publications

References 52 publications

A Novel Sialyltransferase Inhibitor Suppresses FAK/Paxillin Signaling and Cancer Angiogenesis and Metastasis Pathways

A Novel Sialyltransferase Inhibitor Suppresses FAK/Paxillin Signaling and Cancer Angiogenesis and Metastasis Pathways

Smad2/Smad3 in endothelium is indispensable for vascular stability via S1PR1 and N-cadherin expressions

Sphingosine kinase-1 and sphingosine 1-phosphate receptor 2 mediate Bcr-Abl1 stability and drug resistance by modulation of protein phosphatase 2A

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