Ceramidases, roles in sphingolipid metabolism and in health and disease

Coant, Nicolas; Sakamoto, Wataru; Mao, Cungui; Hannun, Yusuf A.

doi:10.1016/j.jbior.2016.10.002

Cited by 201 publications

(159 citation statements)

References 76 publications

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“…While the mechanisms of ceramide function in biological membranes and the biological consequences of ceramide alterations for cellular processes are still poorly understood, overwhelming data point to the role of these sphingolipids as important cellular regulators. Over the last 3 decades ceramides were established as second messengers regulating key cellular processes including cytoskeleton dynamics, endocytosis, protein transport and subcellular localization, cell cycle, autophagy, and apoptosis (Castro et al, 2014; Coant, Sakamoto, Mao, & Hannun, 2017; Dany & Ogretmen, 2015; Mullen, Hannun, & Obeid, 2012). Therefore, ceramides are indispensable for cellular homeostasis and control of fundamental functions, such as proliferation, migration, differentiation, adaptation to stress, survival, and senescence (Hannun & Obeid, 2008, 2017).…”

Section: Introductionmentioning

confidence: 99%

Ceramide Signaling and p53 Pathways

Jeffries¹,

Krupenko

2018

Advances in Cancer Research

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Ceramides, important players in signal transduction, interact with multiple cellular pathways, including p53 pathways. However, the relationship between ceramide and p53 is very complex, and mechanisms underlying their coregulation are diverse and not fully characterized. The role of p53, an important cellular regulator and a transcription factor, is linked to its tumor suppressor function. Ceramides are involved in the regulation of fundamental processes in cancer cells including cell death, proliferation, autophagy, and drug resistance. This regulation, however, can be pro-death or pro-survival depending on cancer type, the balance between ceramide species, the rate of their synthesis and utilization, and the availability of a specific array of downstream targets. This chapter highlights the central role of ceramide in sphingolipid metabolism, its role in cancer, specific effectors in ceramide pathways controlled by p53, and coregulation of ceramide and p53 signaling. We discuss the recent studies, which underscore the function of p53 in the regulation of ceramide pathways and the reciprocal regulation of p53 by ceramide. This complex relationship is based on several molecular mechanisms including the p53-dependent transcriptional regulation of enzymes in sphingolipid pathways, the activation of mutant p53 through ceramide-mediated alternative splicing, as well as modulation of the p53 function through direct and indirect effects on p53 coregulators and downstream targets. Further insight into the connections between ceramide and p53 will allow simultaneous targeting of the two pathways with a potential to yield more efficient anticancer therapeutics.

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Section: Introductionmentioning

confidence: 99%

Ceramide Signaling and p53 Pathways

Jeffries¹,

Krupenko

2018

Advances in Cancer Research

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“…ACER2, which was one of the genes with a high expression in the COPD with emphysema group, is a critical sphingolipid metabolizing enzyme and has been shown to be markedly upregulated and involved in apoptosis in response to various stimuli such as DNA damage 22,23. Ceramide upregulation was suggested to be a possible crucial mediator of alveolar destruction in an animal emphysema model experiment 23.…”

Section: Discussionmentioning

confidence: 99%

Gene expression profile of human lung in a relatively early stage of COPD with emphysema

Jeong

Lim

et al. 2018

COPD

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PurposeAs only some smokers develop COPD with emphysema, we explored the molecular pathogenesis of early-stage COPD with emphysema using gene expression profiling of human lung tissues.Patients and methodsFirst, 110 subjects who had smoked more than ten pack-years were classified into three groups: COPD with emphysema, COPD without emphysema, and healthy smokers. COPD and emphysema were confirmed by post-bronchodilator forced expiratory volume in 1 second/forced vital capacity <0.7 and by chest computed tomography. Lung tissues obtained surgically from the 110 subjects were processed and used for RNA-Seq analysis.ResultsAmong the 110 subjects, 29 had COPD with emphysema, 21 had COPD without emphysema, and 60 were healthy smokers; their mean post-bronchodilator forced expiratory volume in 1 second values were 78%, 80%, and 94%, respectively. Using RNA-Seq, we evaluated 16,676 genes expressed in lung tissues. Among them, 1,226 genes in the COPD with emphysema group and 434 genes in the COPD without emphysema group were differentially expressed genes compared to the expression in healthy smokers. In the COPD with emphysema group, ACER2 and LMAN2L were markedly increased and decreased, respectively. In the COPD without emphysema group, the CHRM3 gene, previously reported to be associated with COPD, and HDAC10 were markedly increased and decreased, respectively.ConclusionOur study identified differences in gene expression in subjects with COPD according to emphysema status using RNA-Seq transcriptome analysis. These findings may have mechanistic implications in COPD.

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“…Interestingly, most of the deletions included in our studies have little effect on the proliferation of wild type cells under non-stress conditions. This suggests that the genetic redundancy of this essential pathway that is conserved and expanded in humans -where at least 6 different genes code for ceramide synthases and 5 for ceramidases (Coant et al, 2016; Wegner et al, 2016)- allows flexibility of regulation during cellular responses to stress.…”

Section: Discussionmentioning

confidence: 99%

Serine-Dependent Sphingolipid Synthesis Is a Metabolic Liability of Aneuploid Cells

et al. 2017

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SUMMARY Aneuploidy disrupts cellular homeostasis. However, the molecular mechanisms underlying the physiological responses and adaptation to aneuploidy are not well understood. Deciphering these mechanisms is important because aneuploidy is associated with diseases including intellectual disability and cancer. Although tumors and mammalian aneuploid cells including several cancer cell lines show altered levels of sphingolipids, the role of sphingolipids in aneuploidy remains unknown. Here we show that ceramides and long-chain bases, sphingolipid molecules that slow proliferation and promote survival, are increased by aneuploidy. Sphingolipid levels are tightly linked to serine synthesis, and inhibiting either serine or sphingolipid synthesis can specifically impair the fitness of aneuploid cells. Remarkably, the fitness of aneuploid cells improves or deteriorates upon genetically decreasing or increasing ceramides, respectively. Combined targeting of serine and sphingolipid synthesis could be exploited to specifically target cancer cells, the vast majority of which are aneuploid.

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Ceramidases, roles in sphingolipid metabolism and in health and disease

Cited by 201 publications

References 76 publications

Ceramide Signaling and p53 Pathways

Ceramide Signaling and p53 Pathways

Gene expression profile of human lung in a relatively early stage of COPD with emphysema

Serine-Dependent Sphingolipid Synthesis Is a Metabolic Liability of Aneuploid Cells

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