Sphingolipids and Bioactive Lipids

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

Deadline for manuscript submissions: closed (31 May 2013) | Viewed by 53179

Special Issue Editors

1. Department of Pharmacology, Stony Brook University, Stony Brook, NY 11794, USA
2. Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA
3. Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
Interests: bioactive lipids; ceramide; sphingolipids; sphingomyelinases; protein kinase C; protein phosphatases
1. Department of Medicine, The State University of New York at Stony Brook, Stony Brook, NY 11794-8155, USA
2. Stony Brook Cancer Center, The State University of New York at Stony Brook, Stony Brook, NY 11794-8155, USA
Interests: bioactive lipid; lipid metabolism; DNA damage response; programmed cell death; cancer initiation; stem cell stemness; inflammation; cancer therapy; non-alcoholic fatty disease; senescence and aging; and neurodegeneration
Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794, USA

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

Manuscript Submission Information

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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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520 KiB  
Article
Altered Sphingolipid Metabolism in Patients with Metastatic Pancreatic Cancer
by Yixing Jiang, Nicole A. DiVittore, Megan M Young, Zhiliang Jia, Keping Xie, Timothy M. Ritty, Mark Kester and Todd E. Fox
Biomolecules 2013, 3(3), 435-448; https://doi.org/10.3390/biom3030435 - 25 Jul 2013
Cited by 41 | Viewed by 7491
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 [...] Read more.
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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1353 KiB  
Article
Regulation of Cytoskeleton Organization by Sphingosine in a Mouse Cell Model of Progressive Ovarian Cancer
by Amy L. Creekmore, C. Lynn Heffron, Bradley P. Brayfield, Paul C. Roberts and Eva M. Schmelz
Biomolecules 2013, 3(3), 386-407; https://doi.org/10.3390/biom3030386 - 16 Jul 2013
Cited by 14 | Viewed by 6690
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 [...] Read more.
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)
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Article
Sphingosine Phosphate Lyase Regulates Murine Embryonic Stem Cell Proliferation and Pluripotency through an S1P2/STAT3 Signaling Pathway
by Gaelen S. Smith, Ashok Kumar and Julie D. Saba
Biomolecules 2013, 3(3), 351-368; https://doi.org/10.3390/biom3030351 - 24 Jun 2013
Cited by 17 | Viewed by 6819
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) [...] Read more.
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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Article
The Roles of Sphingosine Kinase 1 and 2 in Regulating the Metabolome and Survival of Prostate Cancer Cells
by Francesca Tonelli, Manal Alossaimi, Viswanathan Natarajan, Irina Gorshkova, Evgeny Berdyshev, Robert Bittman, David G. Watson, Susan Pyne and Nigel J. Pyne
Biomolecules 2013, 3(2), 316-333; https://doi.org/10.3390/biom3020316 - 10 Jun 2013
Cited by 10 | Viewed by 6551
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, [...] Read more.
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

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1033 KiB  
Review
The Impact of Sphingosine Kinase-1 in Head and Neck Cancer
by Paulette M. Tamashiro, Hideki Furuya, Yoshiko Shimizu, Kayoko Iino and Toshihiko Kawamori
Biomolecules 2013, 3(3), 481-513; https://doi.org/10.3390/biom3030481 - 12 Aug 2013
Cited by 20 | Viewed by 8078
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 [...] Read more.
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)
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560 KiB  
Review
Emerging Role of Sphingosine-1-phosphate in Inflammation, Cancer, and Lymphangiogenesis
by Wei-Ching Huang, Masayuki Nagahashi, Krista P. Terracina and Kazuaki Takabe
Biomolecules 2013, 3(3), 408-434; https://doi.org/10.3390/biom3030408 - 23 Jul 2013
Cited by 57 | Viewed by 10362
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 [...] Read more.
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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385 KiB  
Review
Sphingosine 1-Phosphate and Cancer: Lessons from Thyroid Cancer Cells
by Kid Törnquist
Biomolecules 2013, 3(2), 303-315; https://doi.org/10.3390/biom3020303 - 14 May 2013
Cited by 8 | Viewed by 6456
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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