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Sphingolipid metabolism in cancer signalling and therapy
1Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, South Carolina 29425, USA.
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.
Insights
Sphingolipids like ceramide and sphingosine-1-phosphate (S1P) have opposing roles in cancer. Targeting sphingolipid metabolism offers new strategies to enhance anticancer therapy by promoting cell death and inhibiting survival signals.
Area of Science:
- Biochemistry
- Cancer Biology
- Pharmacology
Background:
- Sphingolipids, ceramide, and sphingosine-1-phosphate (S1P), play critical roles in cancer cell death and survival.
- Dysregulated sphingolipid metabolism is implicated in tumor growth, drug resistance, and metastasis.
Purpose of the Study:
- To review the opposing roles of ceramide and S1P in cancer.
- To summarize mechanisms by which sphingolipids regulate cancer cell death and survival in response to anticancer therapies.
- To highlight therapeutic strategies targeting sphingolipid metabolism and signaling.
Main Methods:
- Review of recent mechanistic studies on sphingolipid metabolism and signaling in cancer.
- Analysis of molecular, genetic, and pharmacological tools targeting sphingolipid pathways.
- Structure-function studies of sphingolipids and their receptors.
Main Results:
- Ceramide induces cancer cell death via apoptosis, necroptosis, and mitophagy.
- Sphingosine kinase-mediated ceramide metabolism to S1P promotes cancer cell growth, drug resistance, and metastasis.
- Targeting sphingolipid enzymes offers therapeutic opportunities.
Conclusions:
- Sphingolipid metabolism and signaling are crucial regulators of cancer progression and response to therapy.
- Targeting ceramide and S1P pathways presents a promising avenue for novel anticancer therapeutics.
- Restoring anti-proliferative ceramide signaling and inhibiting pro-survival S1P signaling can enhance cancer treatment efficacy.
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