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Sphingolipids in Cancer Progression and Therapy
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Sphingolipids in Cancer Progression and Therapy

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: closed (15 November 2020) | Viewed by 23651

Special Issue Editor

Dr. Kazuyuki Kitatani

E-Mail Website
Guest Editor
Laboratory of Immunopharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata 573‐0101, Japan
Interests: sphingolipids; ceramides; sphingotherapy; cancer therapy; cancer biology; cancer metastasis; cellular signaling; cell death; necroptosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue highlights the role of sphingolipids in cancer progression and therapy. Cancer progression is closely associated with cell death, growth, differentiation, angiogenesis, cell motility, metastasis, and inflammatory responses. In recent years, it has become apparent that sphingolipids such as ceramide, sphingosine, and sphingosine-1-phosphate are involved in cancer progression. Especially, ceramide signaling has been implicated in programmed necrosis (necroptosis), whose study may advance the understanding of cancer cell death and ceramide-based cancer therapy. Uncovering the mechanisms by which different sphingolipids regulate cancer pathobiology may promote the development of novel therapies against cancer.

We invite investigators to contribute original research articles as well as review articles that will stimulate continuing efforts to understand the pathobiology of sphingolipids in cancer and provide valuable mechanistic insights that may translate to therapeutic opportunities. This Special Issue will accept basic research, bioinformatic research, translational research, and (pre) clinical research papers.

Dr. Kazuyuki Kitatani
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. Cells 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 2700 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
  • ceramide
  • sphingosine-1-phosphate
  • sphingosine
  • cancer
  • metastasis
  • angiogenesis

Published Papers (6 papers)

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Research

14 pages, 2324 KiB  
Article
Targeting Acid Ceramidase to Improve the Radiosensitivity of Rectal Cancer
by Rachael E. Clifford, Naren Govindarajah, David Bowden, Paul Sutton, Mark Glenn, Mahnaz Darvish-Damavandi, Simon Buczacki, Ultan McDermott, Zdzislaw Szulc, Besim Ogretmen, Jason L. Parsons and Dale Vimalachandran
Cells 2020, 9(12), 2693; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9122693 - 15 Dec 2020
Cited by 14 | Viewed by 3021
Abstract
Previous work utilizing proteomic and immunohistochemical analyses has identified that high levels of acid ceramidase (AC) expression confers a poorer response to neoadjuvant treatment in locally advanced rectal cancer. We aimed to assess the radiosensitising effect of biological and pharmacological manipulation of AC [...] Read more.
Previous work utilizing proteomic and immunohistochemical analyses has identified that high levels of acid ceramidase (AC) expression confers a poorer response to neoadjuvant treatment in locally advanced rectal cancer. We aimed to assess the radiosensitising effect of biological and pharmacological manipulation of AC and elucidate the underlying mechanism. AC manipulation in three colorectal cancer cell lines (HT29, HCT116 and LIM1215) was achieved using siRNA and plasmid overexpression. Carmofur and a novel small molecular inhibitor (LCL521) were used as pharmacological AC inhibitors. Using clonogenic assays, we demonstrate that an siRNA knockdown of AC enhanced X-ray radiosensitivity across all colorectal cancer cell lines compared to a non-targeting control siRNA, and conversely, AC protein overexpression increased radioresistance. Using CRISPR gene editing, we also generated AC knockout HCT116 cells that were significantly more radiosensitive compared to AC-expressing cells. Similarly, two patient-derived organoid models containing relatively low AC expression were found to be comparatively more radiosensitive than three other models containing higher levels of AC. Additionally, AC inhibition using carmofur and LCL521 in three colorectal cancer cell lines increased cellular radiosensitivity. Decreased AC protein led to significant poly-ADP ribose polymerase-1 (PARP-1) cleavage and apoptosis post-irradiation, which was shown to be executed through a p53-dependent process. Our study demonstrates that expression of AC within colorectal cancer cell lines modulates the cellular response to radiation, and particularly that AC inhibition leads to significantly enhanced radiosensitivity through an elevation in apoptosis. This work further solidifies AC as a target for improving radiotherapy treatment of locally advanced rectal cancer. Full article
(This article belongs to the Special Issue Sphingolipids in Cancer Progression and Therapy)
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14 pages, 2826 KiB  
Article
Sphingosine Kinase Blockade Leads to Increased Natural Killer T Cell Responses to Mantle Cell Lymphoma
by Michael S. Lee, Wenji Sun and Tonya J. Webb
Cells 2020, 9(4), 1030; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9041030 - 21 Apr 2020
Cited by 14 | Viewed by 2891
Abstract
Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin’s lymphoma. Despite being responsive to combination chemotherapy, median survival remains around 5 years due to high rates of relapse. Sphingolipid metabolism regulates MCL survival and proliferation and we found that sphingosine-1-phosphate (S1P) is [...] Read more.
Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin’s lymphoma. Despite being responsive to combination chemotherapy, median survival remains around 5 years due to high rates of relapse. Sphingolipid metabolism regulates MCL survival and proliferation and we found that sphingosine-1-phosphate (S1P) is upregulated in MCL cells. Therapeutic targeting of the S1P1 receptor or knockdown of sphingosine kinase 1 (SK1), the enzyme responsible for generating S1P, in human MCL cells results in a significant increase in Natural Killer T (NKT) cell activation. NKT cells recognize glycolipid antigens presented on CD1d and can reduce MCL tumor burden in vivo. Lipidomic studies identified cardiolipin, which has been reported to bind to CD1d molecules, as being upregulated in SK1 knockdown cells. We found that the pretreatment of antigen presenting cells with cardiolipin leads to increased cytokine production by NKT cell hybridomas. Furthermore, the ability of cardiolipin to activate NKT cells was dependent on the structure of its acyl chains. Collectively, these studies delineate novel pathways important for immune recognition of malignant cells and could lead to the development of new treatments for lymphoma. Full article
(This article belongs to the Special Issue Sphingolipids in Cancer Progression and Therapy)
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23 pages, 14995 KiB  
Article
Sphingosine Kinase 1 Regulates the Survival of Breast Cancer Stem Cells and Non-stem Breast Cancer Cells by Suppression of STAT1
by Ling-Wei Hii, Felicia Fei-Lei Chung, Chun Wai Mai, Zong Yang Yee, Hong Hao Chan, Vijay Joseph Raja, Noah Elias Dephoure, Nigel J. Pyne, Susan Pyne and Chee-Onn Leong
Cells 2020, 9(4), 886; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9040886 - 04 Apr 2020
Cited by 24 | Viewed by 4390
Abstract
Cancer stem cells (CSCs) represent rare tumor cell populations capable of self-renewal, differentiation, and tumor initiation and are highly resistant to chemotherapy and radiotherapy. Thus, therapeutic approaches that can effectively target CSCs and tumor cells could be the key to efficient tumor treatment. [...] Read more.
Cancer stem cells (CSCs) represent rare tumor cell populations capable of self-renewal, differentiation, and tumor initiation and are highly resistant to chemotherapy and radiotherapy. Thus, therapeutic approaches that can effectively target CSCs and tumor cells could be the key to efficient tumor treatment. In this study, we explored the function of SPHK1 in breast CSCs and non-CSCs. We showed that RNAi-mediated knockdown of SPHK1 inhibited cell proliferation and induced apoptosis in both breast CSCs and non-CSCs, while ectopic expression of SPHK1 enhanced breast CSC survival and mammosphere forming efficiency. We identified STAT1 and IFN signaling as key regulatory targets of SPHK1 and demonstrated that an important mechanism by which SPHK1 promotes cancer cell survival is through the suppression of STAT1. We further demonstrated that SPHK1 inhibitors, FTY720 and PF543, synergized with doxorubicin in targeting both breast CSCs and non-CSCs. In conclusion, we provide important evidence that SPHK1 is a key regulator of cell survival and proliferation in breast CSCs and non-CSCs and is an attractive target for the design of future therapies. Full article
(This article belongs to the Special Issue Sphingolipids in Cancer Progression and Therapy)
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19 pages, 6735 KiB  
Article
Acid Sphingomyelinase Downregulation Enhances Mitochondrial Fusion and Promotes Oxidative Metabolism in a Mouse Model of Melanoma
by Marco Coazzoli, Alessandra Napoli, Paulina Roux-Biejat, Clara De Palma, Claudia Moscheni, Elisabetta Catalani, Silvia Zecchini, Vincenzo Conte, Matteo Giovarelli, Sonia Caccia, Patrizia Procacci, Davide Cervia, Emilio Clementi and Cristiana Perrotta
Cells 2020, 9(4), 848; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9040848 - 31 Mar 2020
Cited by 9 | Viewed by 2812
Abstract
Melanoma is the most severe type of skin cancer. Its unique and heterogeneous metabolism, relying on both glycolysis and oxidative phosphorylation, allows it to adapt to disparate conditions. Mitochondrial function is strictly interconnected with mitochondrial dynamics and both are fundamental in tumour progression [...] Read more.
Melanoma is the most severe type of skin cancer. Its unique and heterogeneous metabolism, relying on both glycolysis and oxidative phosphorylation, allows it to adapt to disparate conditions. Mitochondrial function is strictly interconnected with mitochondrial dynamics and both are fundamental in tumour progression and metastasis. The malignant phenotype of melanoma is also regulated by the expression levels of the enzyme acid sphingomyelinase (A-SMase). By modulating at transcriptional level A-SMase in the melanoma cell line B16-F1 cells, we assessed the effect of enzyme downregulation on mitochondrial dynamics and function. Our results demonstrate that A-SMase influences mitochondrial morphology by affecting the expression of mitofusin 1 and OPA1. The enhanced expression of the two mitochondrial fusion proteins, observed when A-SMase is expressed at low levels, correlates with the increase of mitochondrial function via the stimulation of the genes PGC-1alpha and TFAM, two genes that preside over mitochondrial biogenesis. Thus, the reduction of A-SMase expression, observed in malignant melanomas, may determine their metastatic behaviour through the stimulation of mitochondrial fusion, activity and biogenesis, conferring a metabolic advantage to melanoma cells. Full article
(This article belongs to the Special Issue Sphingolipids in Cancer Progression and Therapy)
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18 pages, 4128 KiB  
Article
Nrp1 is Activated by Konjac Ceramide Binding-Induced Structural Rigidification of the a1a2 Domain
by Seigo Usuki, Yoshiaki Yasutake, Noriko Tamura, Tomohiro Tamura, Kunikazu Tanji, Takashi Saitoh, Yuta Murai, Daisuke Mikami, Kohei Yuyama, Kenji Monde, Katsuyuki Mukai and Yasuyuki Igarashi
Cells 2020, 9(2), 517; https://0-doi-org.brum.beds.ac.uk/10.3390/cells9020517 - 24 Feb 2020
Cited by 3 | Viewed by 4057
Abstract
Konjac ceramide (kCer) is a plant-type ceramide composed of various long-chain bases and α-hydroxyl fatty acids. The presence of d4t,8t-sphingadienine is essential for semaphorin 3A (Sema3A)-like activity. Herein, we examined the three neuropilin 1 (Nrp1) domains (a1a2, b1b2, or c), and found that [...] Read more.
Konjac ceramide (kCer) is a plant-type ceramide composed of various long-chain bases and α-hydroxyl fatty acids. The presence of d4t,8t-sphingadienine is essential for semaphorin 3A (Sema3A)-like activity. Herein, we examined the three neuropilin 1 (Nrp1) domains (a1a2, b1b2, or c), and found that a1a2 binds to d4t,8t-kCer and possesses Sema3A-like activity. kCer binds to Nrp1 with a weak affinity of μM dissociation constant (Kd). We wondered whether bovine serum albumin could influence the ligand–receptor interaction that a1a2 has with a single high affinity binding site for kCer (Kd in nM range). In the present study we demonstrated the influence of bovine serum albumin. Thermal denaturation indicates that the a1a2 domain may include intrinsically disordered region (IDR)-like flexibility. A potential interaction site on the a1 module was explored by molecular docking, which revealed a possible Nrp1 activation mechanism, in which kCer binds to Site A close to the Sema3A-binding region of the a1a2 domain. The a1 module then accesses a2 as the IDR-like flexibility becomes ordered via kCer-induced protein rigidity of a1a2. This induces intramolecular interaction between a1 and a2 through a slight change in protein secondary structure. Full article
(This article belongs to the Special Issue Sphingolipids in Cancer Progression and Therapy)
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19 pages, 2869 KiB  
Article
Macrophage S1PR1 Signaling Alters Angiogenesis and Lymphangiogenesis During Skin Inflammation
by Shahzad Nawaz Syed, Rebecca Raue, Andreas Weigert, Andreas von Knethen and Bernhard Brüne
Cells 2019, 8(8), 785; https://0-doi-org.brum.beds.ac.uk/10.3390/cells8080785 - 28 Jul 2019
Cited by 16 | Viewed by 5840
Abstract
The bioactive lipid sphingosine-1-phosphate (S1P), along with its receptors, modulates lymphocyte trafficking and immune responses to regulate skin inflammation. Macrophages are important in the pathogenesis of psoriasiform skin inflammation and express various S1P receptors. How they respond to S1P in skin inflammation remains [...] Read more.
The bioactive lipid sphingosine-1-phosphate (S1P), along with its receptors, modulates lymphocyte trafficking and immune responses to regulate skin inflammation. Macrophages are important in the pathogenesis of psoriasiform skin inflammation and express various S1P receptors. How they respond to S1P in skin inflammation remains unknown. We show that myeloid specific S1P receptor 1 (S1PR1) deletion enhances early inflammation in a mouse model of imiquimod-induced psoriasis, without altering the immune cell infiltrate. Mechanistically, myeloid S1PR1 deletion altered the formation of IL-1β, VEGF-A, and VEGF-C, and their receptors’ expression in psoriatic skin, which subsequently lead to reciprocal regulation of neoangiogenesis and neolymphangiogenesis. Experimental findings were corroborated in human clinical datasets and in knockout macrophages in vitro. Increased blood vessel but reduced lymph vessel density may explain the exacerbated inflammatory phenotype in conditional knockout mice. These findings assign a novel role to macrophage S1PR1 and provide a rationale for therapeutically targeting local S1P during skin inflammation. Full article
(This article belongs to the Special Issue Sphingolipids in Cancer Progression and Therapy)
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