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Cancers
Special Issues
The Sphingolipid Pathway in Cancer
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The Sphingolipid Pathway in Cancer

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 November 2019) | Viewed by 19670

Special Issue Editors

Prof. Dr. Stuart M. Pitson

E-Mail Website
Guest Editor
Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5000, Australia
Interests: sphingolipids; sphingosine kinase; lipid metabolism; cell signaling; acute myeloid leukaemia; multiple myeloma; glioblastoma
Prof. Nigel Pyne

E-Mail Website
Guest Editor
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral St, Glasgow G40RE, Scotland, UK
Interests: sphingolipids; sphingosine 1-phosphate; sphingosine kinase; dihydroceramide desaturase; sphingosine 1-phosphate receptors; solid tumors; hematological cancer; cell signaling; lipid metabolism
Dr. Melissa Pitman

E-Mail Website
Guest Editor
Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide SA 5001, Australia
Interests: sphingolipids; lipid kinases; drug discovery; biochemistry; protein–protein interactions; cell signaling; ovarian cancer

Special Issue Information

Dear Colleagues,

Sphingolipids have long been known to play critical roles in the properties of cellular membranes. Research over the last three decades, however, has shown a number of sphingolipids to also be important signaling molecules that regulate a wide array of biological processes. In particular, sphingolipids, including but not limited to the ceramides and sphingosine 1-phosphate, have been shown to be important regulators of cell fate, influencing cell survival and proliferation, as well as cell differentiation. For this reason, the sphingolipid pathway has garnered significant interest as a target for anticancer therapies.

This Special Issue of Cancers seeks reviews and original papers that examine the roles of the sphingolipid pathway and its various individual components in cancers. The objective is to highlight the current understanding of the regulation of sphingolipid metabolism and signaling, its impact on cancer initiation, progression and responses to therapy, including chemoresistance, and how this information may be exploited for therapeutic benefit.

Prof. Stuart Pitson
Prof. Nigel Pyne
Dr. Melissa Pitman
Guest Editors

Manuscript Submission Information

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. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short 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 thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly 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 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Sphingolipids
  • Ceramides
  • Sphingosine 1-phosphate
  • Cell signaling
  • Cancer
  • Apoptosis

Published Papers (5 papers)

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Research

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15 pages, 2326 KiB  
Article
Sphingosine 1-Phosphate Receptor 2 Induces Otoprotective Responses to Cisplatin Treatment
by Wei Wang, Muthu K. Shanmugam, Ping Xiang, Ting Yu Amelia Yam, Vineet Kumar, Wee Siong Chew, Jing Kai Chang, Muhammad Zulfaqar Bin Ali, Marie J. Y. Reolo, Yee Xin Peh, Siti Nasuha Binte Abdul Karim, Andrew Y.Y. Tan, Takaomi Sanda, Gautam Sethi and Deron R. Herr
Cancers 2020, 12(1), 211; https://doi.org/10.3390/cancers12010211 - 15 Jan 2020
Cited by 21 | Viewed by 3911
Abstract
Ototoxicity is a major adverse effect of platinum-based chemotherapeutics and currently, there remains a lack of United States Food and Drug Administration-approved therapies to prevent or treat this problem. In our study, we examined the role of the sphingosine 1-phosphate receptor 2 (S1P [...] Read more.
Ototoxicity is a major adverse effect of platinum-based chemotherapeutics and currently, there remains a lack of United States Food and Drug Administration-approved therapies to prevent or treat this problem. In our study, we examined the role of the sphingosine 1-phosphate receptor 2 (S1P2) in attenuating cisplatin-induced ototoxicity in several different animal models and cell lines. We found that ototoxicity in S1P2 knockout mice is dependent on reactive oxygen species (ROS) production and that S1P2 receptor activation with a specific agonist, CYM-5478, significantly attenuates cisplatin-induced defects, including hair cell degeneration in zebrafish and prolonged auditory brainstem response latency in rats. We also evaluated the cytoprotective effect of CYM-5478 across different cell lines and showed that CYM-5478 protects neural-derived cell lines but not breast cancer cells against cisplatin toxicity. We show that this selective protection of CYM-5478 is due to its differential effects on key regulators of apoptosis between neural cells and breast cancer cells. Overall, our study suggests that targeting the S1P2 receptor represents a promising therapeutic approach for the treatment of cisplatin-induced ototoxicity in cancer patients. Full article
(This article belongs to the Special Issue The Sphingolipid Pathway in Cancer)
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15 pages, 1708 KiB  
Article
The Transfer of Sphingomyelinase Contributes to Drug Resistance in Multiple Myeloma
by Sylvia Faict, Inge Oudaert, Ludovic D’Auria, Jonas Dehairs, Ken Maes, Philip Vlummens, Kim De Veirman, Elke De Bruyne, Karel Fostier, Isabelle Vande Broek, Rik Schots, Karin Vanderkerken, Johannes V. Swinnen and Eline Menu
Cancers 2019, 11(12), 1823; https://doi.org/10.3390/cancers11121823 - 20 Nov 2019
Cited by 37 | Viewed by 3412
Abstract
Multiple myeloma (MM) is well-known for the development of drug resistance, leading to relapse. Therefore, finding novel treatment strategies remains necessary. By performing a lipidomics assay on MM patient plasma, we aimed to identify new targets. We observed a dysregulation in the sphingolipid [...] Read more.
Multiple myeloma (MM) is well-known for the development of drug resistance, leading to relapse. Therefore, finding novel treatment strategies remains necessary. By performing a lipidomics assay on MM patient plasma, we aimed to identify new targets. We observed a dysregulation in the sphingolipid metabolism, with the upregulation of several ceramides and downregulation of sphingomyelin. This imbalance suggests an increase in sphingomyelinase, the enzyme responsible for hydrolyzing sphingomyelin into ceramide. We confirmed the upregulation of acid sphingomyelinase (ASM) in primary MM cells. Furthermore, we observed an increase in ASM expression in MM cell lines treated with melphalan or bortezomib, as well as in their exosomes. Exosomes high in ASM content were able to transfer the drug-resistant phenotype to chemosensitive cells, hereby suggesting a tumor-protective role for ASM. Finally, inhibition of ASM by amitriptyline improved drug sensitivity in MM cell lines and primary MM cells. In summary, this study is the first to analyze differences in plasma lipid composition of MM patients and match the observed differences to an upregulation of ASM. Moreover, we demonstrate that amitriptyline is able to inhibit ASM and increase sensitivity to anti-myeloma drugs. This study, therefore, provides a rational to include ASM-targeting-drugs in combination strategies in myeloma patients. Full article
(This article belongs to the Special Issue The Sphingolipid Pathway in Cancer)
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Review

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16 pages, 861 KiB  
Review
Are Glucosylceramide-Related Sphingolipids Involved in the Increased Risk for Cancer in Gaucher Disease Patients? Review and Hypotheses
by Patricia Dubot, Leonardo Astudillo, Nicole Therville, Frédérique Sabourdy, Jérôme Stirnemann, Thierry Levade and Nathalie Andrieu-Abadie
Cancers 2020, 12(2), 475; https://doi.org/10.3390/cancers12020475 - 18 Feb 2020
Cited by 15 | Viewed by 3659
Abstract
The roles of ceramide and its catabolites, i.e., sphingosine and sphingosine 1-phosphate, in the development of malignancies and the response to anticancer regimens have been extensively described. Moreover, an abundant literature points to the effects of glucosylceramide synthase, the mammalian enzyme that converts [...] Read more.
The roles of ceramide and its catabolites, i.e., sphingosine and sphingosine 1-phosphate, in the development of malignancies and the response to anticancer regimens have been extensively described. Moreover, an abundant literature points to the effects of glucosylceramide synthase, the mammalian enzyme that converts ceramide to β-glucosylceramide, in protecting tumor cells from chemotherapy. Much less is known about the contribution of β-glucosylceramide and its breakdown products in cancer progression. In this chapter, we first review published and personal clinical observations that report on the increased risk of developing cancers in patients affected with Gaucher disease, an inborn disorder characterized by defective lysosomal degradation of β-glucosylceramide. The previously described mechanistic links between lysosomal β-glucosylceramidase, β-glucosylceramide and/or β-glucosylphingosine, and various hallmarks of cancer are reviewed. We further show that melanoma tumor growth is facilitated in a Gaucher disease mouse model. Finally, the potential roles of the β-glucosylceramidase protein and its lipidic substrates and/or downstream products are discussed. Full article
(This article belongs to the Special Issue The Sphingolipid Pathway in Cancer)
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25 pages, 2042 KiB  
Review
Targeting the Sphingolipid System as a Therapeutic Direction for Glioblastoma
by Melinda N. Tea, Santosh I. Poonnoose and Stuart M. Pitson
Cancers 2020, 12(1), 111; https://doi.org/10.3390/cancers12010111 - 1 Jan 2020
Cited by 30 | Viewed by 4567
Abstract
Glioblastoma (GBM) is the most commonly diagnosed malignant brain tumor in adults. The prognosis for patients with GBM remains poor and largely unchanged over the last 30 years, due to the limitations of existing therapies. Thus, new therapeutic approaches are desperately required. Sphingolipids [...] Read more.
Glioblastoma (GBM) is the most commonly diagnosed malignant brain tumor in adults. The prognosis for patients with GBM remains poor and largely unchanged over the last 30 years, due to the limitations of existing therapies. Thus, new therapeutic approaches are desperately required. Sphingolipids are highly enriched in the brain, forming the structural components of cell membranes, and are major lipid constituents of the myelin sheaths of nerve axons, as well as playing critical roles in cell signaling. Indeed, a number of sphingolipids elicit a variety of cellular responses involved in the development and progression of GBM. Here, we discuss the role of sphingolipids in the pathobiology of GBM, and how targeting sphingolipid metabolism has emerged as a promising approach for the treatment of GBM. Full article
(This article belongs to the Special Issue The Sphingolipid Pathway in Cancer)
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23 pages, 1451 KiB  
Review
Role of Sphingosylphosphorylcholine in Tumor and Tumor Microenvironment
by Mi Kyung Park and Chang Hoon Lee
Cancers 2019, 11(11), 1696; https://doi.org/10.3390/cancers11111696 - 31 Oct 2019
Cited by 8 | Viewed by 3552
Abstract
Sphingosylphosphorylcholine (SPC) is a unique type of lysosphingolipid found in some diseases, and has been studied in cardiovascular, neurological, and inflammatory phenomena. In particular, SPC's studies on cancer have been conducted mainly in terms of effects on cancer cells, and relatively little consideration [...] Read more.
Sphingosylphosphorylcholine (SPC) is a unique type of lysosphingolipid found in some diseases, and has been studied in cardiovascular, neurological, and inflammatory phenomena. In particular, SPC's studies on cancer have been conducted mainly in terms of effects on cancer cells, and relatively little consideration has been given to aspects of tumor microenvironment. This review summarizes the effects of SPC on cancer and tumor microenvironment, and presents the results and prospects of modulators that regulate the various actions of SPC. Full article
(This article belongs to the Special Issue The Sphingolipid Pathway in Cancer)
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