Role of bioactive sphingolipids in physiology and pathology

Gómez-Larrauri, Ana; Presa, Natalia; Dominguez-Herrera, Asier; Ouro, Alberto; Trueba, Miguel; Gómez-Muñoz, Antonio

doi:10.1042/ebc20190091

Cited by 110 publications

(98 citation statements)

References 105 publications

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“…Similar to its effect in many other cell types [15,34], a low concentration of S1P enhanced cell viability in EGFR+ cells (Figure 2B). Since it has been demonstrated that SK1-generated S1P can act through S1P receptors stimulating cell proliferation and survival [19], we investigated the potential correlation between this "inside-out" signaling of S1P and EGFR+ cell survival.…”

Section: Extracellular S1p Is Responsible For the Resistance To Tmz Of Egfr+ Cellssupporting

confidence: 72%

Extracellular Sphingosine-1-Phosphate Downstream of EGFR Increases Human Glioblastoma Cell Survival

Bassi

Brambilla

Tringali

et al. 2021

IJMS

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Sphingosine-1-phosphate (S1P) is a crucial mediator involved in the progression of different cancers, including glioblastoma multiforme (GBM), the most frequent and deadly human brain tumor, characterized by extensive invasiveness and rapid cell growth. Most of GBMs overexpress the epidermal growth factor receptor (EGFR), and we investigated the possible link between S1P and EGFR signaling pathways, focusing on its role in GBM survival, using the U87MG human cell line overexpressing EGFR (EGFR+). We previously demonstrated that EGFR+ cells have higher levels of extracellular S1P and increased sphingosine kinase-1 (SK1) activity than empty vector expressing cells. Notably, we demonstrated that EGFR+ cells are resistant to temozolomide (TMZ), the standard chemotherapeutic drug in GBM treatment, and the inhibition of SK1 or S1P receptors made EGFR+ cells sensitive to TMZ; moreover, exogenous S1P reverted this effect, thus involving extracellular S1P as a survival signal in TMZ resistance in GBM cells. In addition, both PI3K/AKT and MAPK inhibitors markedly reduced cell survival, suggesting that the enhanced resistance to TMZ of EGFR+ cells is dependent on the increased S1P secretion, downstream of the EGFR-ERK-SK1-S1P pathway. Altogether, our study provides evidence of a functional link between S1P and EGFR signaling pathways enhancing the survival properties of GBM cells.

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Section: Extracellular S1p Is Responsible For the Resistance To Tmz Of Egfr+ Cellssupporting

confidence: 72%

Extracellular Sphingosine-1-Phosphate Downstream of EGFR Increases Human Glioblastoma Cell Survival

Bassi

Brambilla

Tringali

et al. 2021

IJMS

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“…The biology of sphingolipids has been extensively explored in the peripheral system, and the associated pathologies have also been thoroughly investigated; however, despite being major structural components of the brain anatomy, the functional significance of sphingolipid signaling in the CNS remains underexplored. The majority of published data emphasize the involvement of sphingolipids in inflammatory disorders, such as asthma, chronic pain, rheumatoid arthritis, and infections [ 85 ], and some recent findings indicate their role in neuroinflammation and neurodegeneration as well [ 36 , 86 ]. As mentioned earlier, aspirin is the treatment of choice for inflammatory illnesses, which acts as a nonselective inhibitor of COX2 enzymatic activity and resolves inflammation by abrogating the synthesis of prostanoids.…”

Section: Discussionmentioning

confidence: 99%

Novelty of Sphingolipids in the Central Nervous System Physiology and Disease: Focusing on the Sphingolipid Hypothesis of Neuroinflammation and Neurodegeneration

Ayub

Jin

Bae

2021

IJMS

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For decades, lipids were confined to the field of structural biology and energetics as they were considered only structural constituents of cellular membranes and efficient sources of energy production. However, with advances in our understanding in lipidomics and improvements in the technological approaches, astounding discoveries have been made in exploring the role of lipids as signaling molecules, termed bioactive lipids. Among these bioactive lipids, sphingolipids have emerged as distinctive mediators of various cellular processes, ranging from cell growth and proliferation to cellular apoptosis, executing immune responses to regulating inflammation. Recent studies have made it clear that sphingolipids, their metabolic intermediates (ceramide, sphingosine-1-phosphate, and N-acetyl sphingosine), and enzyme systems (cyclooxygenases, sphingosine kinases, and sphingomyelinase) harbor diverse yet interconnected signaling pathways in the central nervous system (CNS), orchestrate CNS physiological processes, and participate in a plethora of neuroinflammatory and neurodegenerative disorders. Considering the unequivocal importance of sphingolipids in CNS, we review the recent discoveries detailing the major enzymes involved in sphingolipid metabolism (particularly sphingosine kinase 1), novel metabolic intermediates (N-acetyl sphingosine), and their complex interactions in CNS physiology, disruption of their functionality in neurodegenerative disorders, and therapeutic strategies targeting sphingolipids for improved drug approaches.

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“…Sphingolipids and long-chain unsaturated fatty acids in particular ranked as top predictors of genital inflammation. Emerging studies have demonstrated that sphingolipids are implicated in multiple pathological processes, such as inflammatory diseases, diabetes, and cancer (58). In a previous report we showed that women with cervical cancer had elevated sphingolipids in the cervicovaginal fluids, suggesting that cancer drives associations of phospholipids with inflammation.…”

Section: Discussionmentioning

confidence: 99%

Integration of multi-omics data improves prediction of cervicovaginal microenvironment in cervical cancer

Bokulich

Łaniewski

Chase

et al. 2020

Preprint

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Emerging evidence suggests that a complex interplay between human papillomavirus (HPV), microbiota, and the cervicovaginal microenvironment contribute to HPV persistence and carcinogenesis. Integration of multiple omics datasets is predicted to provide unique insight into HPV infection and cervical cancer progression. Cervicovaginal specimens were collected from a cohort (n=100) of Arizonan women with cervical cancer, cervical dysplasia, as well as HPV-positive and HPV-negative controls. Microbiome, immunoproteome and metabolome analyses were performed using 16S rRNA gene sequencing, multiplex cytometric bead arrays, and liquid chromatography-mass spectrometry, respectively. Multi-omics integration methods, including neural networks (mmvec) and Random Forest supervised learning, were utilized to explore potential interactions and develop predictive models. Our integrated bioinformatic analyses revealed that cancer biomarker concentrations were reliably predicted by Random Forest regressors trained on microbiome and metabolome features, suggesting close correspondence between the vaginal microbiome, metabolome, and genital inflammation involved in cervical carcinogenesis. Furthermore, we show that features of the microbiome and host microenvironment, including metabolites, microbial taxa, and immune biomarkers are predictive of genital inflammation status, but only weakly to moderately predictive of cervical cancer state. Different feature classes were important for prediction of different phenotypes. Lipids (e.g. sphingolipids and long-chain unsaturated fatty acids) were strong predictors of genital inflammation, whereas predictions of vaginal microbiota and vaginal pH relied mostly on alterations in amino acid metabolism. Finally, we identified key immune biomarkers associated with the vaginal microbiota composition and vaginal pH (MIF and TNF-alpha), as well as genital inflammation (IL-6, IL-10, leptin and VEGF). Integration of multiple different microbiome "omics" data types resulted in modest increases in classifier performance over classifiers trained on the best performing individual omics data type. However, since the most predictive features cannot be known a priori, a multi-omics approach can still yield insights that might not be possible with a single data type. Additionally, integrating multiple omics datasets provided insight into different features of the cervicovaginal microenvironment and host response. Multi-omics is therefore likely to remain essential for realizing the advances promised by microbiome research.

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Role of bioactive sphingolipids in physiology and pathology

Cited by 110 publications

References 105 publications

Extracellular Sphingosine-1-Phosphate Downstream of EGFR Increases Human Glioblastoma Cell Survival

Extracellular Sphingosine-1-Phosphate Downstream of EGFR Increases Human Glioblastoma Cell Survival

Novelty of Sphingolipids in the Central Nervous System Physiology and Disease: Focusing on the Sphingolipid Hypothesis of Neuroinflammation and Neurodegeneration

Integration of multi-omics data improves prediction of cervicovaginal microenvironment in cervical cancer

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