Sphingolipid metabolism in cancer signalling and therapy

Key Points

  • Sphingolipids are bioactive molecules that have key roles in the regulation of cancer cell signalling to control tumour suppression or survival. Ceramide is a bioeffector molecule that mediates cell death, whereas sphingosine-1-phosphate (S1P) induces tumour cell proliferation, resistance to chemotherapy, radiotherapy or immunotherapy and metastasis.

  • The metabolic network of sphingolipids provides regulatory nodes for controlling cancer growth and/or proliferation in response to cellular stress, including the activation of enzymes that generate the tumour suppressor ceramide and/or inhibit the conversion of ceramide to S1P or other complex sphingolipids that have pro-survival and/or anti-apoptotic function, such as sphingomyelin and glucosylceramide.

  • Induction of ceramide generation and/or accumulation mediates cancer cell death via apoptosis, necroptosis or mitophagy, which might be regulated by the distinct functions of de novo-generated endogenous ceramides with different fatty acyl chain lengths. Downstream mechanisms of ceramide in induction of cell death are regulated mainly by its subcellular localization, trafficking and lipid–protein binding between ceramide and target proteins such as phosphatase 2A inhibitor I2PP2A or microtubule-associated protein 1 light chain 3β (LC3B) in cancer cells.

  • The metabolic conversion of ceramide to S1P increases cancer cell survival via G protein-coupled S1P receptor (S1PR)-dependent or S1PR-independent oncogenic signalling. Systemic S1P mediates host–cancer cell communication to increase tumour metastasis, which involves the function of protein spinster homologue 2 (SPNS2) for S1P secretion from lymphoid endothelial cells and S1PR1-dependent or S1PR2-dependent signalling in cancer cells to induce migration and/or evade immune-cell-mediated cytotoxicity.

  • There are also receptor-independent roles of endogenous S1P; direct S1P–protein interactions, including with histone deacetylase 1 (HDAC1), HDAC2 and telomerase, regulate cancer cell growth and proliferation.

  • Targeting sphingolipid metabolism to activate pro-cell death ceramide signalling and/or inhibit pro-survival S1P signalling using genetic, molecular, immunological or pharmacological tools provides novel strategies for the development of new therapies — including immunotherapies — for various cancer types, some of which are under current evaluation in active clinical trials.

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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Figure 1: Pathways of sphingolipid metabolism and key enzymes.
Figure 2: Intracellular ceramide signalling in cancer cell death and tumour suppression.
Figure 3: Oncogenic S1P–S1PR1-5 signalling.
Figure 4: Receptor-independent intracellular S1P signalling.

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Acknowledgements

The author thanks N. Oleinik and C. Frichtel for their editorial assistance. The author is also thankful to Z. Szulc for his assistance with the chemical structures of sphingolipid molecules and the members of his laboratory for their helpful discussions. The author apologizes to those investigators whose publications were not mentioned in this Review owing to space limitations. This work is supported by research grants from the NIH (R01-DE16572, R01-CA88932, R01-CA173687 and P01-CA203628), and the South Carolina SmartState Endowment for Lipidomics and Drug Discovery.

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Glossary

Lactosylceramide

A type of ceramide (globoside) that is incorporated with lactose.

Glycosphingolipids

A subtype of glycolipids that contain amino alcohol sphingosine, which include cerebrosides, gangliosides and globosides.

Lysosomal storage diseases

A group of inherited metabolic disorders that result from defective lysosomal function and are mainly associated with accumulation of sphingolipids and/or glycosphingolipids.

Pheochromocytoma

A rare tumour of the adrenal gland.

Eicosanoid

A class of bioactive lipid derived from polyunsaturated fatty acids, which include prostaglandins, leukotrienes and thromboxanes.

Hexosylceramides

Ceramide molecules that contain a hexosyl group, such as monohexosylceramide (glucosylceramide).

Necroptosis

A programmed necrosis involving receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3 signalling that ruptures the plasma membrane, leading to cellular rupture and death.

Mitochondrial outer membrane permeabilization

(MOMP). A key step in the execution of apoptosis, regulated by BCL-2 family member proteins, that leads to the release of pro-cell death factors, such as cytochrome c, from the internal mitochondrial membrane to engage with caspase signalling.

Mitophagy

A form of autophagy that selectively degrades damaged mitochondria through the actions of double-membraned autophagosomes.

Survival autophagy

A type of macroautophagy that mediates a vacuolar and self-digesting mechanism responsible for the removal of damaged proteins and/or organelles by double-membraned autophagosomes associated with lysosomes, providing nutrients for cell survival during stress conditions such as starvation.

Mitochondrial fission

The partition of the mitochondrial membrane between two forming daughter mitochondria, which is regulated by a set of proteins including dynamin-related protein 1 (DRP1), parkin and PTEN-induced putative kinase 1 (PINK1).

Lymphopaenia

A condition defined by the presence of abnormally low levels of lymphocytes (white blood cells or immune cells) in the blood.

Gastrointestinal radiation syndrome

A syndrome caused by exposure to high doses of radiation that induces substantial cell death in the gastrointestinal tract.

Allogeneic haematopoietic stem cell transplantation

(Allo-HSCT). A transplantation of multipotent haematopoietic stem cells derived from bone marrow, peripheral blood or umbilical cord blood from a genetically dissimilar donor for the treatment of patients with multiple myeloma or leukaemia.

Graft-versus-host disease

A medical complication that might occur after allogeneic haematopoietic stem cell transplantation, in which transplanted immune cells from a donor (graft) recognize the recipient (host) tissues as foreign (non-self), attacking the host cells and resulting in tissue or organ damage.

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Ogretmen, B. Sphingolipid metabolism in cancer signalling and therapy. Nat Rev Cancer 18, 33–50 (2018). https://doi.org/10.1038/nrc.2017.96

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