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Ceramide-orchestrated signalling in cancer cells

Key Points

  • Ceramide is a sphingolipid consisting of sphingosine, an 18-carbon unsaturated amino alcohol hydrocarbon chain, which is joined by an amide linkage to a fatty acid of varying chain length and a varying degree of saturation. The type of fatty acyl group that is attached often dictates the biological activities of ceramide.

  • Through its capacity to induce programmed cell death (apoptosis), ceramide can function as a potent tumour suppressor lipid. Ceramide can also limit cancer cell proliferation by blocking cell cycle transition. Ceramide can also instigate autophagic responses in cancer cells; however, these may yield survival or lethal outcomes.

  • Cancer cells exert tight control over the metabolism of ceramide. As a survival mode, cancer cells upregulate enzymes that metabolize ceramide, which results in muted apoptotic responses and/or the promotion of mitogenicity, depending on the routes by which ceramide is metabolized.

  • Ceramide signalling in cancer cells enlists extrinsic signalling, which originates outside the cell, or intrinsic signalling (also known as the mitochondrial pathway) that originates from within the cell, to signal to downstream beacons of cellular response. These responses can be caspase (protease)-dependent or caspase-independent.

  • Key players in ceramide signalling in cancer are protein phosphatase 2A, p38, JUN N-terminal kinase (JNK), AKT, protein kinase Cζ (PKCζ) and survivin, proteins that communicate and reinforce tumour cell demise and/or the arrest of the cell cycle at G1 and G2 phases.

  • Because of its ability to induce apoptosis, ceramide holds promise as an anticancer agent. Ceramide-based therapies are being developed through the use of ceramide-generating agents, such as fenretinide, and by the use of exogenous cell-permeable short-chain ceramides, such as C6 ceramide. With both avenues, the effect of ceramide can be magnified by the inclusion of agents that block cancer cell-mediated elimination of ceramide.

Abstract

One crucial barrier to progress in the treatment of cancer has been the inability to control the balance between cell proliferation and apoptosis: enter ceramide. Discoveries over the past 15 years have elevated this sphingolipid to the lofty position of a regulator of cell fate. Ceramide, it turns out, is a powerful tumour suppressor, potentiating signalling events that drive apoptosis, autophagic responses and cell cycle arrest. However, defects in ceramide generation and metabolism in cancer cells contribute to tumour cell survival and resistance to chemotherapy. This Review focuses on ceramide signalling and the targeting of specific metabolic junctures to amplify the tumour suppressive activities of ceramide. The potential of ceramide-based therapeutics in the treatment of cancer is also discussed.

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Figure 1: De novo biosynthesis of ceramide.
Figure 2: Ceramide metabolism and points of intervention.
Figure 3: Extrinsic and intrinsic pathways of ceramide-driven apoptosis in cancer.
Figure 4: Pathways of ceramide-driven autophagic response.
Figure 5: The effect of ceramide on cell cycle progression.

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Acknowledgements

Supported in part through grants from the US National Institutes of Health (GM77391, CA143755), and funding from the Fashion Footwear Association of New York Charitable Foundation (New York, USA) and the Associates for Breast and Prostate Cancer Studies (Los Angeles, USA).

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Correspondence to Samy A. F. Morad or Myles C. Cabot.

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Supplementary information S1

Sphingolipid enzymes that are altered in cancer (PDF 96 kb)

Supplementary information S2

Inhibitors of ceramide metabolism to enhance therapeutic potential of anticancer agents (PDF 126 kb)

Glossary

Sphingolipids

A class of membrane lipids that includes sphingomyelin, which contains an 18-carbon monounsaturated amino alcohol moiety, sphingosine.

Ceramide

The neutral lipid backbone of complex sphingolipids, including glycolipids, which consists of a long-chain amino alcohol, sphingosine, linked to a fatty acid via an amide bond.

Serine palmitoyltransferase

The enzyme that catalyses the first step in the biosynthesis of sphingolipids, the condensation of serine and palmitoyl-CoA.

Ceramidases

Enzymes catalysing hydrolysis of the fatty acid moiety of ceramide, producing sphingosine.

Sphingomyelinase

(SMase). A hydrolase that breaks down sphingomyelin into ceramide and the polar headgroup phosphocholine.

Glucosylceramide synthase

(GCS). Also known as ceramide glucosyltransferase. Catalyses the transfer of UDP-glucose to ceramide to form glucosylceramide, a reaction often used by cancer cells to detoxify ceramide.

Sphingomyelin synthases

(SMSs). The enzymes responsible for the synthesis of sphingomyelin, which use ceramide and phosphatidylcholine (lecithin) as substrates.

Taxanes

A class of antitumour (antimitotic or antimicrotubule) agents derived from Taxus brevifolia (the Pacific yew tree); examples include paclitaxel and docetaxel.

DNA crosslinking agent

Chemicals that bind to strands of DNA that block DNA replication, resulting in DNA replication arrest and tumour cell death. For example, chemotherapeutic agents such as carmustine and nitrogen mustard.

Ceramide-enriched membrane platforms

Ceramide-enriched regions of the plasma membrane that have distinct structural composition that function as platforms to colocalize proteins involved in intracellular signalling.

Inhibitor of apoptosis protein (IAP) family

A family of proteins that function as endogenous inhibitors of apoptosis. These proteins can bind to caspases (executioner proteins) thereby preventing apoptosis.

Mitophagy

A process that removes damaged mitochondria from the cell before leading to cell death (mitochondrial autophagy).

BH3-only family

Members of the BCL-2 pro-apoptotic protein family essential for initiating apoptosis.

Short-chain ceramides

Ceramide analogues consisting of sphingosine linked by an amide bond to a short-chain fatty acid, such as hexanoic acid (6 carbons), and are often used because they are cell-permeable and mimic the effects of natural ceramides.

Autophagolysosome

The digestive vacuole of autophagy that is generated by the fusion of lysosome and autophagic vacuole.

Cathepsins

Enzymes that catalyse hydrolytic cleavage of peptide bonds in proteins leading to protein degradation.

Triple-negative breast cancer

A heterogenous group of breast cancers that do not express oestrogen receptor, progesterone receptor and HER2, and are thus refractory to endocrine therapy such as tamoxifen and trastuzumab.

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Morad, S., Cabot, M. Ceramide-orchestrated signalling in cancer cells. Nat Rev Cancer 13, 51–65 (2013). https://doi.org/10.1038/nrc3398

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