Special Issue "Sphingolipids and Bioactive Lipids"

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A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (31 May 2013)

Special Issue Editors

Guest Editor
Prof. Dr. Yusuf A. Hannun

Director of Stony Brook Cancer Center, Vice Dean for Cancer Medicine, Joel Kenny Professor of Medicine, Stony Brook University, Health Science Center, Stony Brook, NY 11794, USA
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Fax: +1 631 444 2661
Interests: bioactive lipids; ceramide; sphingolipids; sphingomyelinases; protein kinase C; protein phosphatases
Guest Editor
Dr. Cungui Mao

Lipid Cancer Lab, Department of Medicine. SUNY at Stony Brook, Mail Code 8155, Stony Brook, NY 11794-8155, USA
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Guest Editor
Dr. Chiara Luberto

Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794, USA
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Special Issue Information

Dear Colleagues,

It has been approximately one hundred and thirty years since the identification of the first sphingolipid, and the progress in understanding the roles and functions of this enigmatic class of lipids has since been remarkable. With this scientific progress came the unanticipated realization of the great complexity of sphingolipid metabolism with current estimates of  several thousand individual sphingolipid molecular species. Many of these compounds are now recognized as bioactive molecules, often with opposing roles, such as ceramide and sphingosine 1-phosphate, and their specific roles in regulation of many fundamental cellular processes, such as cell proliferation, differentiation and cell death is now widely documented. Thus, it comes as no surprise that altered regulation of sphingolipid metabolism has been found to contribute to the development and/or maintenance of pathological conditions, such as cancer, neurodegenerative diseases, diabetes and metabolic regulation, and infections and immunity. This explosion in research has necessitated a more focused approach on specific pathways and specific pathobiologies. Thus, the aim of this special issue is to focus on the roles and functions of the various sphingolipids in the development, progression and treatment of various cancers. Still, we have only scratched the surface. With these considerations in mind, we invite the submission of research and review articles that address the proposed topic by covering basic as well as clinical aspects of sphingolipids or sphingolipid-metabolizing enzymes in the context of the various cancers. We also encourage the submission of articles documenting the use of innovative techniques/approaches for quantitative analysis, imaging and in vivo modulation of sphingolipids that could exert a significant impact in the general understanding of the exciting topic.

We look forward to reading your contributions.

Prof. Dr. Yusuf Hannun
Dr. Cungui Mao
Dr. Chiara Luberto
Guest Editors

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed Open Access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 600 CHF (Swiss Francs). English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.

Keywords

  • autophagy
  • ER stress
  • cell adhesion
  • cell migration
  • metastasis
  • inflammation
  • ceramide
  • sphingosine
  • sphingosine-1-phosphate (S1P)
  • lipid signaling
  • cell proliferation
  • cell differentiation
  • apoptosis
  • cancer metabolism
  • cancer energetics
  • angiogenesis
  • oncogenes
  • cancer animal models
  • cancer therapeutics
  • lipidomics

Published Papers (7 papers)

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Research

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Open AccessArticle Altered Sphingolipid Metabolism in Patients with Metastatic Pancreatic Cancer
Biomolecules 2013, 3(3), 435-448; doi:10.3390/biom3030435
Received: 23 May 2013 / Revised: 10 July 2013 / Accepted: 24 July 2013 / Published: 25 July 2013
Cited by 5 | PDF Full-text (520 KB) | HTML Full-text | XML Full-text
Abstract
Although numerous genetic mutations and amplifications have been identified in pancreatic cancer, much of the molecular pathogenesis of the disease remains undefined. While proteomic and transcriptomic analyses have been utilized to probe and characterize pancreatic tumors, lipidomic analyses have not been applied to
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Although numerous genetic mutations and amplifications have been identified in pancreatic cancer, much of the molecular pathogenesis of the disease remains undefined. While proteomic and transcriptomic analyses have been utilized to probe and characterize pancreatic tumors, lipidomic analyses have not been applied to identify perturbations in pancreatic cancer patient samples. Thus, we utilized a mass spectrometry-based lipidomic approach, focused towards the sphingolipid class of lipids, to quantify changes in human pancreatic cancer tumor and plasma specimens. Subgroup analysis revealed that patients with positive lymph node metastasis have a markedly higher level of ceramide species (C16:0 and C24:1) in their tumor specimens compared to pancreatic cancer patients without nodal disease or to patients with pancreatitis. Also of interest, ceramide metabolites, including phosphorylated (sphingosine- and sphinganine-1-phosphate) and glycosylated (cerebroside) species were elevated in the plasma, but not the pancreas, of pancreatic cancer patients with nodal disease. Analysis of plasma level of cytokine and growth factors revealed that IL-6, IL-8, CCL11 (eotaxin), EGF and IP10 (interferon inducible protein 10, CXCL10) were elevated in patients with positive lymph nodes metastasis, but that only IP10 and EGF directly correlated with several sphingolipid changes. Taken together, these data indicate that sphingolipid metabolism is altered in human pancreatic cancer and associated with advanced disease. Assessing plasma and/or tissue sphingolipids could potentially risk stratify patients in the clinical setting. Full article
(This article belongs to the Special Issue Sphingolipids and Bioactive Lipids)
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Open AccessArticle Regulation of Cytoskeleton Organization by Sphingosine in a Mouse Cell Model of Progressive Ovarian Cancer
Biomolecules 2013, 3(3), 386-407; doi:10.3390/biom3030386
Received: 3 June 2013 / Revised: 4 July 2013 / Accepted: 8 July 2013 / Published: 16 July 2013
Cited by 3 | PDF Full-text (1353 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Ovarian cancer is a multigenic disease and molecular events driving ovarian cancer progression are not well established. We have previously reported the dysregulation of the cytoskeleton during ovarian cancer progression in a syngeneic mouse cell model for progressive ovarian cancer. In the present
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Ovarian cancer is a multigenic disease and molecular events driving ovarian cancer progression are not well established. We have previously reported the dysregulation of the cytoskeleton during ovarian cancer progression in a syngeneic mouse cell model for progressive ovarian cancer. In the present studies, we investigated if the cytoskeleton organization is a potential target for chemopreventive treatment with the bioactive sphingolipid metabolite sphingosine. Long-term treatment with non-toxic concentrations of sphingosine but not other sphingolipid metabolites led to a partial reversal of a cytoskeleton architecture commonly associated with aggressive cancer phenotypes towards an organization reminiscent of non-malignant cell phenotypes. This was evident by increased F-actin polymerization and organization, a reduced focal adhesion kinase expression, increased a-actinin and vinculin levels which together led to the assembly of more mature focal adhesions. Downstream focal adhesion signaling, the suppression of myosin light chain kinase expression and hypophosphorylation of its targets were observed after treatment with sphingosine. These results suggest that sphingosine modulate the assembly of actin stress fibers via regulation of focal adhesions and myosin light chain kinase. The impact of these events on suppression of ovarian cancer by exogenous sphingosine and their potential as molecular markers for treatment efficacy warrants further investigation. Full article
(This article belongs to the Special Issue Sphingolipids and Bioactive Lipids)
Open AccessArticle Sphingosine Phosphate Lyase Regulates Murine Embryonic Stem Cell Proliferation and Pluripotency through an S1P2/STAT3 Signaling Pathway
Biomolecules 2013, 3(3), 351-368; doi:10.3390/biom3030351
Received: 18 April 2013 / Revised: 15 June 2013 / Accepted: 20 June 2013 / Published: 24 June 2013
Cited by 2 | PDF Full-text (503 KB) | HTML Full-text | XML Full-text
Abstract
Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that activates a family of G protein coupled-receptors (GPCRs) implicated in mammalian development, angiogenesis, immunity and tissue regeneration. S1P functions as a trophic factor for many cell types, including embryonic stem cells (ESCs). Sphingosine phosphate lyase (SPL)
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Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that activates a family of G protein coupled-receptors (GPCRs) implicated in mammalian development, angiogenesis, immunity and tissue regeneration. S1P functions as a trophic factor for many cell types, including embryonic stem cells (ESCs). Sphingosine phosphate lyase (SPL) is an intracellular enzyme that catalyzes the irreversible degradation of S1P. We found SPL to be highly expressed in murine ESCs (mESCs). To investigate the role of SPL in mESC biology, we silenced SPL in mESCs via stable transfection with a lentiviral SPL-specific short hairpin RNA (shRNA) construct. SPL-knockdown (SPL-KD) mESCs showed a 5-fold increase in cellular S1P levels, increased proliferation rates and high expression of cell surface pluripotency markers SSEA1 and OCT4 compared to vector control cells. Compared to control mESCs, SPL-KD cells showed robust activation of STAT3 and a 10-fold increase in S1P2 expression. Inhibition of S1P2 or STAT3 reversed the proliferation and pluripotency phenotypes of SPL-KD mESCs. Further, inhibition of S1P2 attenuated, in a dose-dependent fashion, the high levels of OCT4 and STAT3 activation observed in SPL-KD mESCs. Finally, we showed that SPL-KD cells are capable of generating embryoid bodies from which muscle stem cells, called satellite cells, can be isolated. These findings demonstrate an important role for SPL in ESC homeostasis and suggest that SPL inhibition could facilitate ex vivo ESC expansion for therapeutic purposes. Full article
(This article belongs to the Special Issue Sphingolipids and Bioactive Lipids)
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Open AccessArticle The Roles of Sphingosine Kinase 1 and 2 in Regulating the Metabolome and Survival of Prostate Cancer Cells
Biomolecules 2013, 3(2), 316-333; doi:10.3390/biom3020316
Received: 9 May 2013 / Revised: 3 June 2013 / Accepted: 4 June 2013 / Published: 10 June 2013
Cited by 4 | PDF Full-text (343 KB) | HTML Full-text | XML Full-text
Abstract
We have previously shown that treatment of androgen-sensitive LNCaP cells with the sphingosine kinase (SK) inhibitor SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole) induces the proteasomal degradation of two N-terminal variants of SK1 (SK1a and SK1b), increases C22:0-ceramide and diadenosine 5′,5′′′-P1,
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We have previously shown that treatment of androgen-sensitive LNCaP cells with the sphingosine kinase (SK) inhibitor SKi (2-(p-hydroxyanilino)-4-(p-chlorophenyl)thiazole) induces the proteasomal degradation of two N-terminal variants of SK1 (SK1a and SK1b), increases C22:0-ceramide and diadenosine 5′,5′′′-P1,P3-triphosphate (Ap3A) and reduces S1P levels, and promotes apoptosis. We have now investigated the effects of three SK inhibitors (SKi, (S)-FTY720 vinylphosphonate, and (R)-FTY720 methyl ether) on metabolite and sphingolipid levels in androgen-sensitive LNCaP and androgen-independent LNCaP-AI prostate cancer cells. The 51 kDa N-terminal variant of SK1 (SK1b) evades the proteasome in LNCaP-AI cells, and these cells do not exhibit an increase in C22:0-ceramide or Ap3A levels and do not undergo apoptosis in response to SKi. In contrast, the SK inhibitor (S)-FTY720 vinylphosphonate induces degradation of SK1b in LNCaP-AI, but not in LNCaP cells. In LNCaP-AI cells, (S)-FTY720 vinylphosphonate induces a small increase in C16:0-ceramide levels and cleavage of polyADPribose polymerase (indicative of apoptosis). Surprisingly, the level of S1P is increased by 7.8- and 12.8-fold in LNCaP and LNCaP-AI cells, respectively, on treatment with (S)-FTY720 vinylphosphonate. Finally, treatment of androgen-sensitive LNCaP cells with the SK2-selective inhibitor (R)-FTY720 methyl ether increases lysophosphatidylinositol levels, suggesting that SK2 may regulate lyso-PI metabolism in prostate cancer cells. Full article
(This article belongs to the Special Issue Sphingolipids and Bioactive Lipids)
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Review

Jump to: Research

Open AccessReview The Impact of Sphingosine Kinase-1 in Head and Neck Cancer
Biomolecules 2013, 3(3), 481-513; doi:10.3390/biom3030481
Received: 1 July 2013 / Revised: 2 August 2013 / Accepted: 3 August 2013 / Published: 12 August 2013
Cited by 2 | PDF Full-text (1033 KB) | HTML Full-text | XML Full-text
Abstract
Head and neck squamous cell carcinoma (HNSCC) has a high reoccurrence rate and an extremely low survival rate. There is limited availability of effective therapies to reduce the rate of recurrence, resulting in high morbidity and mortality of advanced cases. Late presentation, delay
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Head and neck squamous cell carcinoma (HNSCC) has a high reoccurrence rate and an extremely low survival rate. There is limited availability of effective therapies to reduce the rate of recurrence, resulting in high morbidity and mortality of advanced cases. Late presentation, delay in detection of lesions, and a high rate of metastasis make HNSCC a devastating disease. This review offers insight into the role of sphingosine kinase-1 (SphK1), a key enzyme in sphingolipid metabolism, in HNSCC. Sphingolipids not only play a structural role in cellular membranes, but also modulate cell signal transduction pathways to influence biological outcomes such as senescence, differentiation, apoptosis, migration, proliferation, and angiogenesis. SphK1 is a critical regulator of the delicate balance between proliferation and apoptosis. The highest expression of SphK1 is found in the advanced stage of disease, and there is a positive correlation between SphK1 expression and recurrent tumors. On the other hand, silencing SphK1 reduces HNSCC tumor growth and sensitizes tumors to radiation-induced death.  Thus, SphK1 plays an important and influential role in determining HNSCC proliferation and metastasis. We discuss roles of SphK1 and other sphingolipids in HNSCC development and therapeutic strategies against HNSCC. Full article
(This article belongs to the Special Issue Sphingolipids and Bioactive Lipids)
Open AccessReview Emerging Role of Sphingosine-1-phosphate in Inflammation, Cancer, and Lymphangiogenesis
Biomolecules 2013, 3(3), 408-434; doi:10.3390/biom3030408
Received: 11 June 2013 / Revised: 4 July 2013 / Accepted: 8 July 2013 / Published: 23 July 2013
Cited by 13 | PDF Full-text (560 KB) | HTML Full-text | XML Full-text
Abstract
The main function of the lymphatic system is to control and maintain fluid homeostasis, lipid transport, and immune cell trafficking. In recent years, the pathological roles of lymphangiogenesis, the generation of new lymphatic vessels from preexisting ones, in inflammatory diseases and cancer progression
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The main function of the lymphatic system is to control and maintain fluid homeostasis, lipid transport, and immune cell trafficking. In recent years, the pathological roles of lymphangiogenesis, the generation of new lymphatic vessels from preexisting ones, in inflammatory diseases and cancer progression are beginning to be elucidated. Sphingosine-1-phosphate (S1P), a bioactive lipid, mediates multiple cellular events, such as cell proliferation, differentiation, and trafficking, and is now known as an important mediator of inflammation and cancer. In this review, we will discuss recent findings showing the emerging role of S1P in lymphangiogenesis, in inflammation, and in cancer. Full article
(This article belongs to the Special Issue Sphingolipids and Bioactive Lipids)
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Open AccessReview Sphingosine 1-Phosphate and Cancer: Lessons from Thyroid Cancer Cells
Biomolecules 2013, 3(2), 303-315; doi:10.3390/biom3020303
Received: 19 April 2013 / Revised: 3 May 2013 / Accepted: 6 May 2013 / Published: 14 May 2013
Cited by 3 | PDF Full-text (385 KB) | HTML Full-text | XML Full-text
Abstract
Sphingomyelin is found in the cell membrane of all eukaryotic cells, and was for a long time considered merely as a structural component. However, during the last two decades, metabolites of sphingomyelin, especially sphingosine 1-phosphate (S1P), have proven to be physiologically significant regulators
[...] Read more.
Sphingomyelin is found in the cell membrane of all eukaryotic cells, and was for a long time considered merely as a structural component. However, during the last two decades, metabolites of sphingomyelin, especially sphingosine 1-phosphate (S1P), have proven to be physiologically significant regulators of cell function. Through its five different G protein-coupled receptors, S1P regulates a wide array of cellular processes, ranging from stimulating cellular proliferation and migration, to the inhibition of apoptosis and induction of angiogenesis and modulation of cellular calcium homeostasis. Many of the processes regulated by S1P are important for normal cell physiology, but may also induce severe pathological conditions, especially in malignancies like cancer. Thus, understanding S1P signaling mechanisms has been the aim of a multitude of investigations. Great interest has also been shown in understanding the action of sphingosine kinase (SphK), i.e., the kinase phosphorylating sphingosine to S1P, and the interactions between S1P and growth factor signaling. In the present review, we will discuss recent findings regarding the possible importance of S1P and SphK in the etiology of thyroid cancer. Although clinical data is still scarce, our in vitro findings suggest that S1P may function as a “double-edged sword”, as the receptor profile of thyroid cancer cells largely determines whether S1P stimulates or blocks cellular migration. We will also discuss the interactions between S1P- and VEGF-evoked signaling, and the importance of a S1P1-VEGF receptor 2 complex in thyroid cancer cells. Full article
(This article belongs to the Special Issue Sphingolipids and Bioactive Lipids)
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