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Cancers
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The Role of Ceramide Synthases in Cancers
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The Role of Ceramide Synthases in Cancers

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 20487

Special Issue Editor

Prof. Dr. Sabine Groesch

E-Mail Website
Guest Editor
Faculty of Medicine, Institute of Clinical Pharmacology, Goethe-University Frankfurt, 60590 Frankfurt, Germany
Interests: lipids, sphingolipids; prostanoids; colon cancer; colitis; ceramide synthase

Special Issue Information

Dear Colleagues,

Ceramide synthases (CerS) are essential enzymes of the sphingolipid pathway involved in sphingolipid de novo synthesis, as well as in the salvage pathway. Although several publications about CerS in cancer development or cancer treatment have already been published, there are still many unanswered questions. This upcoming Special Issue will bring together the current state of knowledge in the field of CerS and ceramides in cancer formation. Original work and reviews that focus on CerS and ceramides of distinct chain length in cancer development or cancer treatment are welcome and will be combined in this Special Issue to give the reader a comprehensive overview of the most recent findings concerning this topic with its many facets.

Dr. Sabine Groesch
Guest Editor

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

  • cancer
  • ceramide synthase
  • ceramide
  • chemotherapy
  • radiation therapy
  • sphingolipid
  • metastasis
  • tumor development

Published Papers (5 papers)

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Research

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12 pages, 1709 KiB  
Article
Ceramide Synthase 6 Maximizes p53 Function to Prevent Progeny Formation from Polyploid Giant Cancer Cells
by Ping Lu, Shai White-Gilbertson, Gyda Beeson, Craig Beeson, Besim Ogretmen, James Norris and Christina Voelkel-Johnson
Cancers 2021, 13(9), 2212; https://doi.org/10.3390/cancers13092212 - 5 May 2021
Cited by 14 | Viewed by 2539
Abstract
Polyploid giant cancer cells (PGCC) constitute a transiently senescent subpopulation of cancer cells that arises in response to stress. PGCC are capable of generating progeny via a primitive, cleavage-like cell division that is dependent on the sphingolipid enzyme acid ceramidase (ASAH1). The goal [...] Read more.
Polyploid giant cancer cells (PGCC) constitute a transiently senescent subpopulation of cancer cells that arises in response to stress. PGCC are capable of generating progeny via a primitive, cleavage-like cell division that is dependent on the sphingolipid enzyme acid ceramidase (ASAH1). The goal of this study was to understand differences in sphingolipid metabolism between non-polyploid and polyploid cancer cells to gain an understanding of the ASAH1-dependence in the PGCC population. Steady-state and flux analysis of sphingolipids did not support our initial hypothesis that the ASAH1 product sphingosine is rapidly converted into the pro-survival lipid sphingosine-1-phosphate. Instead, our results suggest that ASAH1 activity is important for preventing the accumulation of long chain ceramides such as C16-ceramide. We therefore determined how modulation of C16-ceramide, either through CerS6 or p53, a known PGCC suppressor and enhancer of CerS6-derived C16-ceramide, affected PGCC progeny formation. Co-expression of the CerS6 and p53 abrogated the ability of PGCC to form offspring, suggesting that the two genes form a positive feedback loop. CerS6 enhanced the effect of p53 by significantly increasing protein half-life. Our results support the idea that sphingolipid metabolism is of functional importance in PGCC and that targeting this signaling pathway has potential for clinical intervention. Full article
(This article belongs to the Special Issue The Role of Ceramide Synthases in Cancers)
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14 pages, 1743 KiB  
Article
C6 Ceramide (d18:1/6:0) as a Novel Treatment of Cutaneous T Cell Lymphoma
by Raphael Wilhelm, Timon Eckes, Gergely Imre, Stefan Kippenberger, Markus Meissner, Dominique Thomas, Sandra Trautmann, Jean-Philippe Merlio, Edith Chevret, Roland Kaufmann, Josef Pfeilschifter, Alexander Koch and Manuel Jäger
Cancers 2021, 13(2), 270; https://doi.org/10.3390/cancers13020270 - 13 Jan 2021
Cited by 8 | Viewed by 2680
Abstract
Cutaneous T cell lymphomas (CTCLs) represent a heterogeneous group of T cell lymphomas that primarily affect the skin. The most frequent forms of CTCL are mycosis fungoides and Sézary syndrome. Both are characterized by frequent recurrence, developing chronic conditions and high mortality with [...] Read more.
Cutaneous T cell lymphomas (CTCLs) represent a heterogeneous group of T cell lymphomas that primarily affect the skin. The most frequent forms of CTCL are mycosis fungoides and Sézary syndrome. Both are characterized by frequent recurrence, developing chronic conditions and high mortality with a lack of a curative treatment. In this study, we evaluated the effect of short-chain, cell-permeable C6 Ceramide (C6Cer) on CTCL cell lines and keratinocytes. C6Cer significantly reduced cell viability of CTCL cell lines and induced cell death via apoptosis and necrosis. In contrast, primary human keratinocytes and HaCaT keratinocytes were less affected by C6Cer. Both keratinocyte cell lines showed higher expressions of ceramide catabolizing enzymes and HaCaT keratinocytes were able to metabolize C6Cer faster and more efficiently than CTCL cell lines, which might explain the observed protective effects. Along with other existing skin-directed therapies, C6Cer could be a novel well-tolerated drug for the topical treatment of CTCL. Full article
(This article belongs to the Special Issue The Role of Ceramide Synthases in Cancers)
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19 pages, 4275 KiB  
Article
Ceramide Synthase 5 Deficiency Aggravates Dextran Sodium Sulfate-Induced Colitis and Colon Carcinogenesis and Impairs T-Cell Activation
by Khadija El-Hindi, Sebastian Brachtendorf, Jennifer Christina Hartel, Stephanie Oertel, Kerstin Birod, Sandra Trautmann, Dominique Thomas, Thomas Ulshöfer, Andreas Weigert, Olaf Utermöhlen, Martin Krönke and Sabine Grösch
Cancers 2020, 12(7), 1753; https://doi.org/10.3390/cancers12071753 - 1 Jul 2020
Cited by 16 | Viewed by 3123
Abstract
Ceramide synthase 5 is one of six enzymes that catalyze the production of ceramides from sphingosine or sphinganine. Ceramides are important components of cell membranes and act as signaling molecules. Previously it has been shown that ceramide synthase 6 and 2 influence colitis [...] Read more.
Ceramide synthase 5 is one of six enzymes that catalyze the production of ceramides from sphingosine or sphinganine. Ceramides are important components of cell membranes and act as signaling molecules. Previously it has been shown that ceramide synthase 6 and 2 influence colitis in several animal models with sometimes opposite effects. Here, we investigated the disease course of dextran sodium sulfate-induced acute colitis and azoxymethane/dextran sodium sulfate-induced colitis-associated colon cancer in mice with global ceramide synthase 5 knockout (CerS5-ko) or with ceramide synthase 5 knockout restricted to the colon epithelium (CerS5fl/fl VilCre). We monitored disease development and analyzed colon barrier function as well as the immune cell status in these mice. CerS5-ko mice but not CerS5fl/fl-VilCre mice were more susceptible to acute and chronic inflammation. However, the cell barrier function of colon epithelial cells was not disturbed by downregulation of ceramide synthase 5. Instead, untreated CerS5-ko mice displayed reduced numbers of CD3+ immune cells in the spleen, colon, and blood, especially of intraepithelial CD8+ T-cells, which was not obvious in CerS5fl/fl Vil Cre mice. Reduced T-cell number in colon tissue of CerS5-ko mice was accompanied by a reduced expression of IL-1β, IFNγ, and IL-4. In vitro investigations revealed that knockdown of ceramide synthase 5 in T-cells impaired T-cell activation. In summary, we show that CerS5-ko mice were more susceptible to dextran sodium sulfate-induced colitis and azoxymethane/dextran sodium sulfate-induced colitis-associated colon cancer. A reduced number of T-cells in the colon epithelium that was already the case in untreated CerS5-ko mice might have contributed to this effect. Full article
(This article belongs to the Special Issue The Role of Ceramide Synthases in Cancers)
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Review

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13 pages, 1509 KiB  
Review
Implication of Ceramide Kinase/C1P in Cancer Development and Progression
by Laura Camacho, Alberto Ouro, Ana Gomez-Larrauri, Arkaitz Carracedo and Antonio Gomez-Muñoz
Cancers 2022, 14(1), 227; https://doi.org/10.3390/cancers14010227 - 4 Jan 2022
Cited by 14 | Viewed by 3448
Abstract
Cancer cells rewire their metabolic programs to favor biological processes that promote cell survival, proliferation, and dissemination. Among this relevant reprogramming, sphingolipid metabolism provides metabolites that can favor or oppose these hallmarks of cancer. The sphingolipid ceramide 1-phosphate (C1P) and the enzyme responsible [...] Read more.
Cancer cells rewire their metabolic programs to favor biological processes that promote cell survival, proliferation, and dissemination. Among this relevant reprogramming, sphingolipid metabolism provides metabolites that can favor or oppose these hallmarks of cancer. The sphingolipid ceramide 1-phosphate (C1P) and the enzyme responsible for its biosynthesis, ceramide kinase (CERK), are well established regulators of cell growth and survival in normal, as well as malignant cells through stress-regulated signaling pathways. This metabolite also promotes cell survival, which has been associated with the feedback regulation of other antitumoral sphingolipids or second messengers. C1P also regulates cancer cell invasion and migration of different types of cancer, including lung, breast, pancreas, prostate, or leukemia cells. More recently, CERK and C1P have been implicated in the control of inflammatory responses. The present review provides an updated view on the important role of CERK/C1P in the regulation of cancer cell growth, survival, and dissemination. Full article
(This article belongs to the Special Issue The Role of Ceramide Synthases in Cancers)
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20 pages, 1623 KiB  
Review
The Role of Ceramide Metabolism and Signaling in the Regulation of Mitophagy and Cancer Therapy
by Megan Sheridan and Besim Ogretmen
Cancers 2021, 13(10), 2475; https://doi.org/10.3390/cancers13102475 - 19 May 2021
Cited by 47 | Viewed by 7601
Abstract
Sphingolipids are bioactive lipids responsible for regulating diverse cellular functions such as proliferation, migration, senescence, and death. These lipids are characterized by a long-chain sphingosine backbone amide-linked to a fatty acyl chain with variable length. The length of the fatty acyl chain is [...] Read more.
Sphingolipids are bioactive lipids responsible for regulating diverse cellular functions such as proliferation, migration, senescence, and death. These lipids are characterized by a long-chain sphingosine backbone amide-linked to a fatty acyl chain with variable length. The length of the fatty acyl chain is determined by specific ceramide synthases, and this fatty acyl length also determines the sphingolipid’s specialized functions within the cell. One function in particular, the regulation of the selective autophagy of mitochondria, or mitophagy, is closely regulated by ceramide, a key regulatory sphingolipid. Mitophagy alterations have important implications for cancer cell proliferation, response to chemotherapeutics, and mitophagy-mediated cell death. This review will focus on the alterations of ceramide synthases in cancer and sphingolipid regulation of lethal mitophagy, concerning cancer therapy. Full article
(This article belongs to the Special Issue The Role of Ceramide Synthases in Cancers)
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