IDENTIFICATION AND QUANTITATION OF p.-CHLOROPHENOXYACETAMIDE, A METABOLITE OF IPROCLOZIDE, IN HUMAN URINE

Leenheer, A.P. De; Sagher, R.M. De; Cruyl, Annie A.; A, Claeys

doi:10.1016/b978-0-08-021308-8.51087-5

Cited by 8 publications

(8 citation statements)

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“…3B). Importantly, this is well within physiological ATRA concentrations (20). Consistent with the observed increase in nSMase2 expression, ATRA stimulation of MCF-7 cells also significantly increased nSMase2 at the protein level (Fig.…”

Section: Atra-induced Growth Arrest Occurs Subsequent To Cer Generatisupporting

confidence: 69%

Neutral Sphingomyelinase-2 Mediates Growth Arrest by Retinoic Acid through Modulation of Ribosomal S6 Kinase

Clarke

Mediwala

Jenkins

et al. 2011

Journal of Biological Chemistry

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All-trans-retinoic acid (ATRA) induces growth arrest of many cell types. Previous studies have reported that ATRA can modulate cellular sphingolipids, but the role of sphingolipids in the ATRA response is not clear. Using MCF-7 cells as a model system, we show that ATRA stimulates an increase in ceramide levels followed by G 0 /G 1 growth arrest. Notably, induction of nSMase2 was the primary effect of ATRA on the sphingolipid network and was both time-and dose-dependent. Importantly, pretreatment with nSMase2 siRNA significantly inhibited ATRA effects on ceramide levels and growth arrest. In contrast, nSMase2 overexpression was sufficient to increase ceramide levels and induce G 0 /G 1 growth arrest of asynchronous MCF-7 cells. Surprisingly, neither ATRA stimulation nor nSMase2 overexpression had significant effects on classical cell cycle regulators such as p21/WAF1 or retinoblastoma. In contrast, ATRA suppressed phosphorylation of ribosomal S6 kinase (S6K) and its downstream targets S6 and eIF4B. Importantly, these effects were significantly inhibited by nSMase2 siRNA. Reciprocally, nSMase2 overexpression was sufficient to suppress S6K phosphorylation and signaling. Notably, neither ATRA effects nor nSMase2 effects on S6K phosphorylation required the ceramide-activated protein phosphatase PP2A, previously identified as important for S6K regulation. Finally, nSMase2 overexpression was sufficient to decrease translation as measured by methionine incorporation and analysis of polyribosome profiles. Taken together, these results implicate nSMase2 as a major component of ATRA-induced growth arrest of MCF-7 cells and identify S6K as a novel downstream target of nSMase2.Sphingolipids such as ceramide (Cer) 2 are a class of bioactive lipids implicated in a variety of physiological processes. In particular, Cer is thought to be involved in apoptosis, inflammation, and the cellular response to cytokines and other stresses (1). Cer production can occur through multiple pathways and is under tight control within the cell. Sphingomyelinases (SMases) produce Cer through hydrolysis of sphingomyelin and are considered important mediators of stress-induced Cer production (2). Currently, three families of SMases have been identified and are classified by the pH optima of their activity. Of these, both acid and neutral SMases (N-SMases) have been reported to contribute to stress and cytokine-induced Cer production (2, 3).Currently, four mammalian N-SMases have been cloned and characterized: nSMase1, nSMase2, nSMase3, and the recently identified mitochondria-associated nSMase. Of these, studies have implicated nSMase2 in the acute responses to cytokines, chemotherapeutic drugs, and oxidative stress (2). Importantly, emerging evidence is beginning to suggest a more protracted mode of nSMase2 regulation involving changes in nSMase2 gene expression. For example, increased nSMase2 expression has been demonstrated in confluence-induced growth arrest of MCF-7 cells (4) and in rat 3Y1 cells where the CCA1 gene (for cell confluence arr...

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Section: Atra-induced Growth Arrest Occurs Subsequent To Cer Generatisupporting

confidence: 69%

Neutral Sphingomyelinase-2 Mediates Growth Arrest by Retinoic Acid through Modulation of Ribosomal S6 Kinase

Clarke

Mediwala

Jenkins

et al. 2011

Journal of Biological Chemistry

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“…Isolated B cells were cultured in RPMI medium 1640 supplemented with 10% heat-inactivated FBS, 5 ϫ 10 Ϫ5 M 2-mercaptoethanol, 100 units͞ml of penicillin, and 100 g͞ml streptomycin (Life Technologies, Carlsbad, CA), at 37°C in a 5% CO 2 incubator. The RA was diluted with medium and added to cells at a concentration of 10 nM, similar to its physiological concentration in plasma (35). (36).…”

Section: Methodsmentioning

confidence: 99%

Vitamin A and immune function: Retinoic acid modulates population dynamics in antigen receptor and CD38-stimulated splenic B cells

Chen

Ross

2005

Proc. Natl. Acad. Sci. U.S.A.

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“…In contrast, the G value of TBARS formation was irradiation, by reverse phase HPLC, with spectrophotometric detec-0.022 + 0.002 p.mol j-1 and 0.038 + 0.003 pmol j-1 for LDL tion at 292 nm [27] in LDL as already described [23].…”

Section: Ldl Oxidation By Y-radiolysis Of Watermentioning

confidence: 99%

Increased susceptibility of low‐density lipoprotein (LDL) to oxidation by γ‐radiolysis with age

Khalil

Wagner²,

Lacombe

et al. 1996

FEBS Letters

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examine the effect of age on the susceptibility to free radical Abstract The susceptibifity to oxidation of freshly isolated oxidation of LDL. To this end, we compared the susceptibility LDL from healthy normolipidemic individuals in three age groups was estimated by exposure of LDL to ionizing radiation of LDL isolated from healthy, normolipidemic individuals followed by analyses of vitamin E, TBARS, conjugated dienes, toward radiation-induced oxidation in an attempt to find facand fluorescent products. The results clearly showed that LDL tors responsible for the association of atherosclerosis with from elderly subjects was the most susceptible to oxidative aging. damage in vitro. In particular, the greater susceptibifity of LDL from elderly subjects in comparison to that from young subjects may be attributed to the much lower (4-fold) concentration of 2. Materials and methods LDL vitamin E in the elderly subjects. The present study reinforces the notion that the susceptibility of LDL to oxidation 2.1. Reagents increases with age.Acetic acid, sulfuric acid n-butanol, sodium phosphate, thiobarbituric acid, methanol and hexane were purchased from Fisher (Mont-

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IDENTIFICATION AND QUANTITATION OF p.-CHLOROPHENOXYACETAMIDE, A METABOLITE OF IPROCLOZIDE, IN HUMAN URINE

Cited by 8 publications

References 0 publications

Neutral Sphingomyelinase-2 Mediates Growth Arrest by Retinoic Acid through Modulation of Ribosomal S6 Kinase

Neutral Sphingomyelinase-2 Mediates Growth Arrest by Retinoic Acid through Modulation of Ribosomal S6 Kinase

Vitamin A and immune function: Retinoic acid modulates population dynamics in antigen receptor and CD38-stimulated splenic B cells

Increased susceptibility of low‐density lipoprotein (LDL) to oxidation by γ‐radiolysis with age

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