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Cited by 1,207Sphingolipid Metabolism and SignalingCancer, Lipids, and MetabolismLysosomal Storage Disorders Research

Sphingolipid metabolism in cancer signalling and therapy

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Ogretmen, Besim·2018·Nature Reviews Cancer
DOI 10.1038/nrc.2017.96PMC PMC5818153
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Abstract

Sphingolipids, including the two central bioactive lipids ceramide and sphingosine-1-phosphate (S1P), have opposing roles in regulating cancer cell death and survival, respectively, and there have been exciting developments in understanding how sphingolipid metabolism and signalling regulate these processes in response to anticancer therapy. Recent studies have provided mechanistic details of the roles of sphingolipids and their downstream targets in the regulation of tumour growth and response to chemotherapy, radiotherapy and/or immunotherapy using innovative molecular, genetic and pharmacological tools to target sphingolipid signalling nodes in cancer cells. For example, structure-function-based studies have provided innovative opportunities to develop mechanism-based anticancer therapeutic strategies to restore anti-proliferative ceramide signalling and/or inhibit pro-survival S1P-S1P receptor (S1PR) signalling. This Review summarizes how ceramide-induced cellular stress mediates cancer cell death through various mechanisms involving the induction of apoptosis, necroptosis and/or mitophagy. Moreover, the metabolism of ceramide for S1P biosynthesis, which is mediated by sphingosine kinase 1 and 2, and its role in influencing cancer cell growth, drug resistance and tumour metastasis through S1PR-dependent or receptor-independent signalling are highlighted. Finally, studies targeting enzymes involved in sphingolipid metabolism and/or signalling and their clinical implications for improving cancer therapeutics are also presented.

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Cited by

Sorted by citations

Authors
Ogretmen, B.
Venue
Nature Reviews Cancer
Publisher
Springer Science and Business Media LLC
Published
2017-11-17
Volume
18
Issue
1
Pages
33-50
ISSN
  • 1474-175X (ISSN-L)
  • 1474-1768
DOI
10.1038/nrc.2017.96
PMC
PMC5818153
OpenAlex
W2769383666
Cited by
1,207
References
4
Citations by year
2026: 119 · 2025: 163 · 2024: 162 · 2023: 146 · 2022: 162 · 2021: 153 · 2020: 138 · 2019: 100 · 2018: 62 · 2017: 2
FWCI
7.78
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature reviews. Cancer (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Cancer Institute (R01CA173687, R01CA088932, P01CA203628)
  • National Institute of Dental and Craniofacial Research (R01DE016572)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
Keywords
sphingolipid metabolism, ceramide, sphingosine-1-phosphate, S1P receptors, cancer cell death, apoptosis, necroptosis, mitophagy, sphingosine kinase 1, sphingosine kinase 2, drug resistance, tumour metastasis, cancer immunotherapy, radiotherapy response, chemotherapy response, anticancer agents
MeSH terms
Animals, Ceramides, Humans, Lysophospholipids, Neoplasms, Sphingolipids, Sphingosine, Signal Transduction, Apoptosis, Drug Resistance, Neoplasm

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