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Biologically active sphingolipids in cancer pathogenesis and treatment

Key Points

  • The sphingolipids ceramide and sphingosine-1-phosphate (S1P) function as effector molecules, and have important roles in stimulus/agonist-mediated signalling and the regulation of many cellular processes.

  • Ceramide, the central molecule in sphingolipid metabolism, mediates antiproliferative responses such as growth inhibition, apoptosis, differentiation, modulation of telomerase activity and telomere length, and senescence. Conversely, S1P induces proliferation, transformation, angiogenesis and cell motility.

  • A network of specialized and compartmentalized enzymes regulates the levels of ceramide and S1P. These enzymes serve as transducers that couple the actions of numerous extra- and intracellular signals to sphingolipid-mediated responses.

  • Attenuation of ceramide levels and/or increased levels of S1P are increasingly implicated in various stages of cancer pathogenesis, including an anti-apoptotic phenotype, metastasis and escape from senescence.

  • Small-molecule inhibitors of enzymes involved in ceramide clearance specifically induce ceramide accumulation and could present a novel therapeutic modality for the treatment of human cancers, including the reversal of drug resistance.

Abstract

Biologically active sphingolipids have key roles in the regulation of several fundamental biological processes that are integral to cancer pathogenesis. Recent significant progress in understanding biologically active sphingolipid synthesis, specifically within ceramide and sphingosine-1-phosphate (S1P)-mediated pathways, has identified crucial roles for these molecules both in cancer development and progression. Ceramide — a central molecule in sphingolipid metabolism — in effect functions as a tumour-suppressor lipid, inducing antiproliferative and apoptotic responses in various cancer cells. Conversely, S1P induces responses that, on aggregate, render S1P a tumour-promoting lipid. These discoveries are paving the way for the advancement of anticancer therapies.

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Figure 1: Pathways of sphingolipid metabolism.
Figure 2: Ceramide-regulated targets and pathways.
Figure 3: Targets and pathways regulated by S1P.
Figure 4: Compartmentalized pathways of ceramide signalling.
Figure 5: Roles of ceramide/sphingosine-1-phosphate in specific cancers.

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Acknowledgements

This work was supported by research grants from the National Institutes of Health/National Cancer Institute. We apologize to investigators whose manuscripts could not be cited in this article because of space limitations. We would like to thank L. Wooten, C. E. Senkal and M. Hinson for their assistance during the preparation of the manuscript. We also thank Z. Sculz, D. Perry and N. Marchesini for critically reviewing the manuscript.

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Correspondence to Yusuf A. Hannun.

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DATABASES

Cancer.gov

breast cancer

colon cancer

head and neck cancer

kidney cancer

lung cancer

ovarian cancer

prostate cancer

stomach cancer

uterine cancer

Entrez Gene

AKT

BCL2

caspase-3

caspase 9

cathepsin D

CDK2

CDK4

COX2

c-RAF

FAN

kinase suppressor of RAS

KIP1

Lac1

Lag1

P-gp

phospholipase D

PKCζ

RB

SK1

TNFα

TP53

TRAF2

VEGF

WAF1

FURTHER INFORMATION

Ceramide Web

Glossary

LIPID RAFTS

Dynamic assemblies of cholesterol and sphingolipids in the plasma membrane that are important for amassing signalling complexes or specific aggregations of particular proteins.

MULTIDRUG RESISTANCE

Simultaneous resistance to several structurally unrelated drugs that do not have a common mechanism of action.

CASPASES

A family of cystein proteases that are activated in response to pro-apoptotic signals and cleave a number of specific protein targets, facilitating the rapid induction of apoptosis.

RNAI-MEDIATED KNOCKDOWN

Use of double-stranded RNA to target specific mRNAs for degradation, resulting in sequence-specific post-transcriptional gene silencing.

REACTIVE OXYGEN SPECIES

Highly reactive chemical radicals that are generated as products of oxygen degradation.

CRISIS

A terminal block in cell proliferation in which cells are destined to die because of collapse of telomeres at the end of chromosomes.

SCID MICE

Severe combined immuno-deficient mice used for the development of tumour xenografts.

VASCULAR SPROUTING

The vascular sprouting process is based on endothelial cell migration, proliferation and tube formation during vasculogenesis, which in situ is the differentiation and growth of blood vessels from mesodermal-derived haemangioblasts.

NEOVASCULARIZATION

A form of angiogenesis that is responsible for the remodelling and expansion of the vascular network.

OLIGODEOXYRIBONUCLEOTIDES

Synthetic, short, defined sequences of DNA.

ABC TRANSPORTER

A member of the membrane-spanning transporter protein family containing an ATP-binding cassette (ABC).

EPIDERMOID

A tissue structure that is similar to that of the flattened top layers of cells (squames) in the epidermis of the skin. It can cover tumours arising from the skin and upper oesophagus, and squamous-cell carcinoma of the lung, among others.

ASCITES

Excess fluid in the space between the membranes lining the abdomen and abdominal organs (the peritoneal cavity). Ascites can occur in patients with cancers affecting organs within the peritoneal cavity, that is, ovarian, liver and intestinal cancers.

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Ogretmen, B., Hannun, Y. Biologically active sphingolipids in cancer pathogenesis and treatment. Nat Rev Cancer 4, 604–616 (2004). https://doi.org/10.1038/nrc1411

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