Inhibition of dihydroceramide desaturase activity by the sphingosine kinase inhibitor SKI II

Cingolani, Francesca; Casasampere, Mireia; Sanllehí, Pol; Casas, Josefina; Bujons, Jordi; Fabriás, Gemma

doi:10.1194/jlr.m049759

Cited by 68 publications

(88 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, SK inhibitors [e.g., 2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole, abbreviated as SKi] that inhibit both SK1 and SK2 activity would appear counterproductive (Lim et al 2011b;Loveridge et al 2010;Mielke and Lyketsos 2010). In addition, SKi has been found to increase dihydroceramide levels, possibly by inhibiting dihydroceramide desaturase (Cingolani et al 2014;Loveridge et al 2010). Dihydroceramide might also be linked to autophagy and ER stress, which mediates G0/G1 cell cycle arrest and suppresses cell proliferation (Gagliostro et al 2012).…”

Section: Neurodegenerative Diseasementioning

confidence: 96%

Resveratrol and its oligomers: modulation of sphingolipid metabolism and signaling in disease

et al. 2014

View full text Add to dashboard Cite

Resveratrol, a natural compound endowed with multiple health-promoting effects, has received much attention given its potential for the treatment of cardiovascular, inflammatory, neurodegenerative, metabolic and age-related diseases. However, the translational potential of resveratrol has been limited by its specificity, poor bioavailability and uncertain toxicity. In recent years, there has been an accumulation of evidence demonstrating that resveratrol modulates sphingolipid metabolism. Moreover, resveratrol forms higher order oligomers that exhibit better selectivity and potency in modulating sphingolipid metabolism. This review evaluates the evidence supporting the modulation of sphingolipid metabolism and signaling as a mechanism of action underlying the therapeutic efficacy of resveratrol and oligomers in diseases, such as cancer.

show abstract

Section: Neurodegenerative Diseasementioning

confidence: 96%

Resveratrol and its oligomers: modulation of sphingolipid metabolism and signaling in disease

et al. 2014

View full text Add to dashboard Cite

show abstract

“…1), in a mode that is thought to be indirect. It has been theorised that SKI-II may inhibit an upstream Des1 activator, such as NADH-cytochrome B5 reductase, leading to loss of Des1 activity [52]. Alternatively, SKI-II may inhibit redox-sensitive Des1 via inducing oxidative stress in cells [80,81].…”

Section: Ski-iimentioning

confidence: 99%

“…Indeed, recent studies have discovered a number of important off-targets that impact on interpretation of these previous studies. In particular, it was recently discovered that SKI-II inhibits dihydroceramide desaturase (Des1) [44,52,67,68,80] an enzyme in the de novo sphingolipid synthesis pathway ( Fig. 1), in a mode that is thought to be indirect.…”

Section: Ski-iimentioning

confidence: 99%

“…The findings that a number of potent SK1 inhibitors fail to induce cancer cell death despite effectively reducing cellular S1P levels [45][46][47], as well as discrepancies with SK2-selective inhibitors either increasing [48,49] or decreasing [50,51] circulating S1P levels in mice have necessitated re-evaluation of how rigorously inhibitors need to be assessed for on-and off-target effects, particularly within the sphingolipid pathway. Indeed, important off-targets have been recently reported for a number of commonly-used SK inhibitors [52,53], meaning re-evaluation of previously published work is required in light of this.…”

Section: Introductionmentioning

confidence: 96%

See 1 more Smart Citation

Recent advances in the development of sphingosine kinase inhibitors

Pitman

Costabile

Pitson

2016

Cellular Signalling

View full text Add to dashboard Cite

Sphingosine kinase (SK) 1 and 2 are lipid kinases that catalyse the formation of sphingosine 1-phosphate (S1P), a potent signalling molecule with a wide array of cellular effects. SK1 and 2 have been shown to be up-regulated in tumours and their genetic ablation or inhibition has been shown to slow tumour growth as well as sensitise cancer cells to chemotherapeutics. The SKs have been extensively studied, with a plethora of inhibitors developed that target the sphingosine-binding pocket of the enzyme, some with nanomolar affinities. Recently, inhibitors targeting the ATP pocket of SK have also been described. Here we discuss the development of these new small molecule SK inhibitors, summarise the recent discovery of off-targets effects of many current SK inhibitors, and provide an overview of the usefulness of these inhibitors as in vitro tools and therapeutic agents.

show abstract

“…Dihydroceramide desaturase is the enzyme that catalyses the formation of ceramide from dihydroceramide. The inhibition of dihydroceramide desaturase by SKi (Cingolani et al, 2014) would therefore lead to the accumulation of dihydroceramide and this appears to induce activation of the proteasome. Consistent with this, the dihydroceramide desaturase inhibitor, fenretinide also promotes the degradation of SK1a in androgenindependent LNCaP-AI prostate cancer cells (unpublished data, McNaughton, Pyne and Pyne).…”

Section: Sk2 and T-all--acute Lymphoblastic Leukaemia Is The Most Commentioning

confidence: 99%

Role of sphingosine 1-phosphate receptors, sphingosine kinases and sphingosine in cancer and inflammation

Pyne

McNaughton

Boomkamp

et al. 2016

Advances in Biological Regulation

121

118

View full text Add to dashboard Cite

Abstract--Sphingosine kinase (there are two isoforms, SK1 and SK2) catalyses the formation of sphingosine 1-phosphate (S1P), a bioactive lipid that can be released from cells to activate a family of G protein-coupled receptors, termed S1P 1-5 . In addition, S1P can bind to intracellular target proteins, such as HDAC1/2, to induce cell responses. There is increasing evidence of a role for S1P receptors (e.g. S1P 4 ) and SK1 in cancer, where high expression of these proteins in ER negative breast cancer patient tumours is linked with poor prognosis.Indeed, evidence will be presented here to demonstrate that S1P 4 is functionally linked with SK1 and the oncogene HER2 (ErbB2) to regulate mitogen-activated protein kinase pathways and growth of breast cancer cells. Although much emphasis is placed on SK1 in terms of involvement in oncogenesis, evidence will also be presented for a role of SK2 in both T-cell and B-cell acute lymphoblastic leukemia. In patient T-ALL lymphoblasts and T-ALL cell lines, we have demonstrated that SK2 inhibitors promote T-ALL cell death via autophagy and induce suppression of c-myc and PI3K/AKT pathways. We will also present evidence demonstrating that certain SK inhibitors promote oxidative stress and protein turnover via proteasomal degradative pathways linked with induction of p53-and p21-induced growth 2 arrest. In addition, the SK1 inhibitor, PF-543 exacerbates disease progression in an experimental autoimmune encephalomyelitis mouse model indicating that SK1 functions in an anti-inflammatory manner. Indeed, sphingosine, which accumulates upon inhibition of SK1 activity, and sphingosine-like compounds promote activation of the inflammasome, which is linked with multiple sclerosis, to stimulate formation of the pro-inflammatory mediator, IL-1β. Such sphingosine like compounds could be exploited to produce antagonists that diminish exaggerated inflammation in disease. The therapeutic potential of modifying the SK-S1P receptor pathway in cancer and inflammation will therefore, be reviewed.3

show abstract

Inhibition of dihydroceramide desaturase activity by the sphingosine kinase inhibitor SKI II

Cited by 68 publications

References 80 publications

Resveratrol and its oligomers: modulation of sphingolipid metabolism and signaling in disease

Resveratrol and its oligomers: modulation of sphingolipid metabolism and signaling in disease

Recent advances in the development of sphingosine kinase inhibitors

Role of sphingosine 1-phosphate receptors, sphingosine kinases and sphingosine in cancer and inflammation

Contact Info

Product

Resources

About