Inhibition of sphingosine 1-phosphate lyase activates human keratinocyte differentiation and attenuates psoriasis in mice

Sphingosine phosphate lyase 1 (SGPL1) is a highly conserved enzyme that irreversibly degrades sphingosine-1-phosphate (S1P). Sgpl1-knockout mice fail to develop germ cells, resulting in infertility. However, the molecular mechanism remains unclear. The results of the present study showed that SGPL1 was expressed mainly in granulosa cells, Leydig cells, spermatocytes, and round spermatids. Sgpl1 deletion led to S1P accumulation in the gonads. In the ovary, S1P decreased natriuretic peptide receptor 2 (NPR2) activity in granulosa cells and inhibited early follicle growth. In the testis, S1P increased the levels of cyclin-dependent kinase inhibitor 1A (p21) and apoptosis in Leydig cells, thus resulting in spermatogenesis arrest. These results indicate that Sgpl1 deletion increases intracellular S1P levels, resulting in the arrest of female and male germ cell development via different signaling pathways.

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“…S4d, e ). p21, a factor that inhibits cell proliferation 25 , 26 , was mainly expressed in granulosa cells (Fig. S5 ).…”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, overexpression of SphK increases S1P levels and then enhances the transcription of p21 in human MCF-7 breast cancer cells 24 . p21 can block cell proliferation in the G1 phase 25 , 26 , and promote cell apoptosis in granulocytes 27 .…”

Section: Introductionmentioning

confidence: 99%

Sgpl1 deletion elevates S1P levels, contributing to NPR2 inactivity and p21 expression that block germ cell development

et al. 2021

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“…Thus, under conditions of DNA damage, the phases that go ahead of these checkpoints, G1- and G2-phases, may be prolonged. Recently, it was shown in HEK cells that genetic suppression of SGPL1 by siRNA arrested the cell cycle at the G1-phase and activated cell differentiation [ 23 ]. In line with this, we had shown before that SGPL1-mediated Ki-67 loss in SGPL1 siRNA treated DLD-cells undergoes epithelial differentiation by increasing Cytokeratin 20 islets in monolayers and enhancing production of F-actin and E-cadherin [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

S1P Lyase Regulates Intestinal Stem Cell Quiescence via Ki-67 and FOXO3

Schwiebs

Faqar-Uz-Zaman

Juan

et al. 2021

IJMS

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Background: Reduction of the Sphingosine-1-phosphate (S1P) degrading enzyme S1P lyase 1 (SGPL1) initiates colorectal cancer progression with parallel loss of colon function in mice. We aimed to investigate the effect of SGPL1 knockout on the stem cell niche in these mice. Methods: We performed immunohistochemical and multi-fluorescence imaging on tissue sections of wildtype and SGPL1 knockout colons under disease conditions. Furthermore, we generated SGPL1 knockout DLD-1 cells (SGPL1−/−M.Ex1) using CRISPR/Cas9 and characterized cell cycle and AKT signaling pathway via Western blot, immunofluorescence, and FACS analysis. Results: SGPL1 knockout mice were absent of anti-Ki-67 staining in the stem cell niche under disease conditions. This was accompanied by an increase of the negative cell cycle regulator FOXO3 and attenuation of CDK2 activity. SGPL1−/−M.Ex1 cells show a similar FOXO3 increase but no arrest of proliferation, although we found a suppression of the PDK1/AKT signaling pathway, a prolonged G1-phase, and reduced stem cell markers. Conclusions: While already established colon cancer cells find escape mechanisms from cell cycle arrest, in vivo SGPL1 knockout in the colon stem cell niche during progression of colorectal cancer can contribute to cell cycle quiescence. Thus, we propose a new function of the S1P lyase 1 in stemness.

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“…Subcutaneous administration of an SPL inhibitor in an imiquimod-induced mouse model of psoriasis was as effective as cyclosporine at decreasing redness and epidermal thickness [ 257 ]. In the DSS/azoxymethane (DSS/AOM) mouse model of colitis-associated cancer, gut epithelium-specific knockout of Sgpl1 resulted in increased disease severity and tumor formation accompanied by increased numbers of macrophages and Th17 T cells [ 258 ].…”

Section: S1p Metabolismmentioning

confidence: 99%

“…An important finding was that after trial initiation, a protocol amendment was needed requiring fasting blood glucose below 160 mg/dL because of dose-limiting hyperglycemia [ 320 ]. Experimentally, ABC suppressed the development of cancer in the DSS/AOM colon cancer model, decreased chemoresistance in breast and ovarian cancer models, and suppressed inflammation in models of arthritis and lupus [ 257 , 321 – 327 ]. Some ABC efficacy may be due to its accumulation in tumor tissues, since the half-life in human plasma is only 5.5 h [ 319 ].…”

Section: Biosynthetic Enzymesmentioning

confidence: 99%

Druggable Sphingolipid Pathways: Experimental Models and Clinical Opportunities

Blaho

2020

Druggable Lipid Signaling Pathways

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Intensive research in the field of sphingolipids has revealed diverse roles in cell biological responses and human health and disease. This immense molecular family is primarily represented by the bioactive molecules ceramide, sphingosine, and sphingosine 1-phosphate (S1P). The flux of sphingolipid metabolism at both the subcellular and extracellular levels provides multiple opportunities for pharmacological intervention. The caveat is that perturbation of any single node of this highly regulated flux may have effects that propagate throughout the metabolic network in a dramatic and sometimes unexpected manner. Beginning with S1P, the receptors for which have thus far been the most clinically tractable pharmacological targets, this review will describe recent advances in therapeutic modulators targeting sphingolipids, their chaperones, transporters, and metabolic enzymes.

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Inhibition of sphingosine 1-phosphate lyase activates human keratinocyte differentiation and attenuates psoriasis in mice

Cited by 27 publications

References 44 publications

Sgpl1 deletion elevates S1P levels, contributing to NPR2 inactivity and p21 expression that block germ cell development

Sgpl1 deletion elevates S1P levels, contributing to NPR2 inactivity and p21 expression that block germ cell development

S1P Lyase Regulates Intestinal Stem Cell Quiescence via Ki-67 and FOXO3

Druggable Sphingolipid Pathways: Experimental Models and Clinical Opportunities

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