Ceramide Kinase Contributes to Proliferation but not to Prostaglandin E&lt;sub&gt;2&lt;/sub&gt; Formation in Renal Mesangial Cells and Fibroblasts

Pastukhov, Oleksandr; Schwalm, Stephanie; Römer, Isolde; Zangemeister‐Wittke, Uwe; Pfeilschifter, Josef; Huwiler, Andrea

doi:10.1159/000362989

Cited by 30 publications

(20 citation statements)

References 59 publications

(73 reference statements)

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“…Moreover, in human tissues of wound healing, C1P levels increased during the early healing stage and correlated with increased proliferation and migration of fibroblasts [39]. Altogether, this contradicts data from renal fibroblasts isolated from CerK deficient mice, as these cells showed strongly reduced proliferation rates compared to their wildtype counterparts [40].…”

Section: Discussionmentioning

confidence: 76%

Ceramide Kinase Is Upregulated in Metastatic Breast Cancer Cells and Contributes to Migration and Invasion by Activation of PI 3-Kinase and Akt

Schwalm

Erhardt

Römer

et al. 2020

IJMS

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Ceramide kinase (CerK) is a lipid kinase that converts the proapoptotic ceramide to ceramide 1-phosphate, which has been proposed to have pro-malignant properties and regulate cell responses such as proliferation, migration, and inflammation. We used the parental human breast cancer cell line MDA-MB-231 and two single cell progenies derived from lung and bone metastasis upon injection of the parental cells into immuno-deficient mice. The lung and the bone metastatic cell lines showed a marked upregulation of CerK mRNA and activity when compared to the parental cell line. The metastatic cells also had increased migratory and invasive activity, which was dose-dependently reduced by the selective CerK inhibitor NVP-231. A similar reduction of migration was seen when CerK was stably downregulated with small hairpin RNA (shRNA). Conversely, overexpression of CerK in parental MDA-MB-231 cells enhanced migration, and this effect was also observed in the non-metastatic cell line MCF7 upon CerK overexpression. On the molecular level, CerK overexpression increased the activation of protein kinase Akt. The increased migration of CerK overexpressing cells was mitigated by the CerK inhibitor NVP-231, by inhibition of the phosphoinositide 3-kinase (PI3K)/Akt pathway and the Rho kinase, but not by inhibition of the classical extracellular signal-regulated kinase (ERK) pathway. Altogether, our data demonstrate for the first time that CerK promotes migration and invasion of metastatic breast cancer cells and that targeting of CerK has potential to counteract metastasis in breast cancer.

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Section: Discussionmentioning

confidence: 76%

Ceramide Kinase Is Upregulated in Metastatic Breast Cancer Cells and Contributes to Migration and Invasion by Activation of PI 3-Kinase and Akt

Schwalm

Erhardt

Römer

et al. 2020

IJMS

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“…Mesangial cell (MC) proliferation and extracellular matrix expansion play a pivotal role in the pathogenesis of glomerulosclerosis. A variety of signaling molecules are involved in proliferation and extracellular matrix expansion of MCs [6,7,8,9]. However, there have been relatively few studies to investigate the role of sympathetic hyperactivity in MCs.…”

Section: Introductionmentioning

confidence: 99%

Alpha1-Adrenergic Receptor Activation Stimulates Calcium Entry and Proliferation via TRPC6 Channels in Cultured Human Mesangial Cells

Kong

Ma²,

Zou³

et al. 2015

Cell Physiol Biochem

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Background and Aims: There is accumulating evidence that sympathetic nervous hyperactivity contributes to the pathogenesis of glomerular sclerosis independent of blood pressure effects. A previous study showed that α₁-adrenoceptor (α₁-AR) antagonists inhibit mesangial cell (MC) proliferation. However, the underlying mechanism remains unclear. Methods and Results: We found that α₁-AR is expressed in a human mesangial cell line. The α₁-AR agonist phenylephrine (PE) induced Ca²⁺ influx as well as release from intracellular Ca²⁺ stores. Blockade of TRPC6 with siRNA, anti-TRPC6 antibodies and a TRPC blocker attenuated the PE-induced [Ca²⁺]_i increase. Additionally, the PE-induced [Ca²⁺]_i increase was phospholipase C dependent. Furthermore, PE induced a [Ca²⁺]_i increase even when the intracellular Ca²⁺ stores were already depleted. This effect was mimicked by an analog of diacylglycerol. These results suggested that, upon α₁-AR stimulation, TRPC6 mediates Ca²⁺ influx via a receptor-operated Ca²⁺ entry mechanism. Finally, TRPC6 contributes to the PE-induced MC proliferation. The mechanisms are associated with the extracellular signal-regulated kinase (ERK) signaling pathway because blockade of TRPC6 and chelation of extracellular Ca²⁺ abrogated PE-induced ERK1/2 abrogated PE-induced ERK1/2 phosphorylation. Conclusion: TRPC6 channels are involved in α₁-AR activation-induced Ca²⁺ entry, which mediates proliferation via ERK signaling in human MCs

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“…In theory, ceramide abundance at the erythrocyte surface could be enhanced by sphingomyelinasedependent formation of ceramide or translocation of existing ceramide to the erythrocyte surface. Ceramide is known to similarly stimulate apoptosis of nucleated cells [37][38][39]. To the best of our knowledge, a stimulating effect of naphthazarin on ceramide abundance has never been reported before.…”

Section: Discussionmentioning

confidence: 86%

Stimulation of Suicidal Erythrocyte Death by Naphthazarin

Aljanadi

Alzoubi

Bissinger

et al. 2015

Basic Clin Pharma Tox

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The 1,4-naphthoquinone derivative naphthazarin may trigger apoptosis and is thus considered for the treatment of malignancy. On the other hand, naphthazarin decreases neurotoxicity. In analogy to apoptosis of nucleated cells, erythrocytes may enter eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and by cell membrane scrambling with translocation of phosphatidylserine to the erythrocyte surface. Signalling leading to triggering of eryptosis include increase in cytosolic Ca 2+ -activity ([Ca 2+ ] i ), ceramide and oxidative stress. The present study explored whether naphthazarin impacts on eryptosis and, if so, to unravel underlying mechanisms. To this end, erythrocyte volume was estimated from forward scatter, phosphatidylserine abundance at the erythrocyte surface from FITC-annexin-V-binding, [Ca 2+ ] i from Fluo3 fluorescence, reactive oxidant species (ROS) from 2 0 ,7 0 -dichlorodihydrofluorescein diacetate (DCFDA) fluorescence and ceramide abundance at the erythrocyte surface from binding of fluorescent antibodies in flow cytometry. As a result, a 24-hr exposure of human erythrocytes to naphthazarin (10 lM) significantly decreased erythrocyte forward scatter, significantly increased the percentage of annexin-V-binding cells, significantly increased ceramide abundance at the erythrocyte surface and significantly increased ROS. The effect of naphthazarin on annexin-V-binding was not significantly blunted by removal of extracellular Ca 2+ . In conclusion, naphthazarin stimulates eryptosis, an effect at least in part due to oxidative stress and enhanced ceramide abundance at the erythrocyte surface.Naphthazarin (5,8-dihydroxy-l,4-naphthoquinone), a naturally available [1,2] 1,4-naphthoquinone derivative [3], has the capacity to induce apoptosis of tumour cells and is thus considered for the treatment of malignancy [3][4][5]. Naphthazarin sensitizes breast cancer cells to the pro-apoptotic effect of radiation [6]. Naphthazarin is effective by various cellular mechanisms including oxidative stress [7,8] [13,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] and accelerated eryptosis contributes to the pathophysiology of several clinical conditions, such as iron deficiency, phosphate depletion, malignancy, metabolic syndrome, diabetes, hepatic and renal insufficiency, dehydration, hyperphosphataemia, haemolytic uraemic syndrome, sepsis, malaria, sickle cell disease, thalassaemia and Wilson's disease [13,[34][35][36].The present study explored whether naphthazarin is able to trigger suicidal death of erythrocytes, that is cells devoid of mitochondria and nuclei, key organelles in the execution of apoptosis. To this end, erythrocytes drawn from healthy volunteers were treated with naphthazarin, and phosphatidylserine surface abundance, cell volume, [Ca 2+ ] i , oxidative stress and ceramide abundance were determined. Materials and MethodsErythrocytes, solutions and chemicals. Fresh Li-Heparinanticoagulated blood samples were kindly provided by the blood...

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Ceramide Kinase Contributes to Proliferation but not to Prostaglandin E<sub>2</sub> Formation in Renal Mesangial Cells and Fibroblasts

Cited by 30 publications

References 59 publications

Ceramide Kinase Is Upregulated in Metastatic Breast Cancer Cells and Contributes to Migration and Invasion by Activation of PI 3-Kinase and Akt

Ceramide Kinase Is Upregulated in Metastatic Breast Cancer Cells and Contributes to Migration and Invasion by Activation of PI 3-Kinase and Akt

Alpha1-Adrenergic Receptor Activation Stimulates Calcium Entry and Proliferation via TRPC6 Channels in Cultured Human Mesangial Cells

Stimulation of Suicidal Erythrocyte Death by Naphthazarin

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