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Review
. 2010 Oct;6(10):1603-24.
doi: 10.2217/fon.10.116.

Sphingolipids and Cancer: Ceramide and sphingosine-1-phosphate in the Regulation of Cell Death and Drug Resistance

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Free PMC article
Review

Sphingolipids and Cancer: Ceramide and sphingosine-1-phosphate in the Regulation of Cell Death and Drug Resistance

Suriyan Ponnusamy et al. Future Oncol. .
Free PMC article

Abstract

Sphingolipids have emerged as bioeffector molecules, controlling various aspects of cell growth and proliferation in cancer, which is becoming the deadliest disease in the world. These lipid molecules have also been implicated in the mechanism of action of cancer chemotherapeutics. Ceramide, the central molecule of sphingolipid metabolism, generally mediates antiproliferative responses, such as cell growth inhibition, apoptosis induction, senescence modulation, endoplasmic reticulum stress responses and/or autophagy. Interestingly, recent studies suggest de novo-generated ceramides may have distinct and opposing roles in the promotion/suppression of tumors, and that these activities are based on their fatty acid chain lengths, subcellular localization and/or direct downstream targets. For example, in head and neck cancer cells, ceramide synthase 6/C(16)-ceramide addiction was revealed, and this was associated with increased tumor growth, whereas downregulation of its synthesis resulted in ER stress-induced apoptosis. By contrast, ceramide synthase 1-generated C(18)-ceramide has been shown to suppress tumor growth in various cancer models, both in situ and in vivo. In addition, ceramide metabolism to generate sphingosine-1-phosphate (S1P) by sphingosine kinases 1 and 2 mediates, with or without the involvement of G-protein-coupled S1P receptor signaling, prosurvival, angiogenesis, metastasis and/or resistance to drug-induced apoptosis. Importantly, recent findings regarding the mechanisms by which sphingolipid metabolism and signaling regulate tumor growth and progression, such as identifying direct intracellular protein targets of sphingolipids, have been key for the development of new chemotherapeutic strategies. Thus, in this article, we will present conclusions of recent studies that describe opposing roles of de novo-generated ceramides by ceramide synthases and/or S1P in the regulation of cancer pathogenesis, as well as the development of sphingolipid-based cancer therapeutics and drug resistance.

Figures

Figure 1
Figure 1. De novo generation of ceramide and its metabolism to generate sphingosine-1-phosphate
The first step of de novo synthesis of ceramide and other complex sphingolipids is the condensation of serine and palmitoyl CoA by SPT, followed by the action of CerS and DES forming ceramide, the central molecule of sphingolipid metabolism. Sphingosine formation occurs via deacylation of ceramide by CDase. Following deacylation, sphingosine is released, which can then be phosphorylated to generate S1P by the action of SK1 or SK2. S1P is hydrolyzed by S1P lyase. Ceramide can also be formed from the degradation of SM by SMases and glycosphingolipids by cerobrosidases. Ceramide is further metabolized for the synthesis of GlcCer by GCS, which is a precursor for lactosylceramide and ganglioside generation. C1P: Ceramide-1-phosphate; CDase: Ceramidase; CerS: Ceramide synthase; DAG: Diacylglycerol; DES: Desaturase; GCS: Glucosylceramide synthase; GlcCer: Glucosylceramide; S1P: Sphingosine-1-phosphate; S1PP: Phosphorylated sphingosine-1 phosphate; SK: Sphingosine kinase; SM: Sphingomyelin; SMase: Sphingomyelinase; SPT: Serine-palmitoyl CoA transferase.
Figure 2
Figure 2. Specificity of ceramide synthase(s) and the diversity of ceramide species
The de novo synthesis of various chain length fatty acids containing ceramide are formed by the action of specific CerS. CerS1 specifically biosynthesizes C18 -ceramide; CerS2 and CerS4 mediate very-long-chain fatty acid-containing ceramide synthesis, such as C22-, C24- and C26-ceramides. Additionally, CerS5 and CerS6 are mostly responsible for the synthesis of chain lengths up to 16, such as C12-, C14- and C16-ceramides. Ceramide is the precursor for S1P. Importantly, these two molecules have opposing functions and are known to regulate each other. In addition, ceramides with different chain lengths might have distinct and sometimes opposing functions in the regulation of tumor progression and/or growth. For example, in HNSCC tumors, while CerS1-generated C18-ceramide inhibits tumor growth, CerS6-mediated C16-ceramide induces tumor growth. CerS: Ceramide synthase; DES: Desaturase; HNSCC: Head and neck squamous cell carcinoma; S1P: Sphingosine-1-phosphate.
Figure 3
Figure 3. Opposing functions of ceramide synthase 1 and 6
CerS6/C16-ceramide accumulation regulates ER homeostasis and stress responses favoring cell proliferation and tumor growth. Conversely, deduction of CerS6/C16-ceramide by RNAi against CerS6 induces ER stress by the ATF6/CHOP arm, which leads to cell death. CerS1/C18-ceramide levels can be increased by the treatment of chemotherapeutic agents, such as GMZ and DOX, which can inhibit tumor cell growth through the induction of autophagy or by directly inducing tumor cell apoptosis. CerS: Ceramide synthase; DOX: Doxorubicin; ER: Endoplasmic reticulum; GMZ: Gemcitabine; HNSCC: Head and neck squamous cell carcinoma.
Figure 4
Figure 4. Regulation of oncogenic c-Myc by protein phosphatase 2A via control of ceramide in normal and cancer cells
In normal cells, ceramide and its binding protein, I2PP2A, which is the inhibitor for PP2A, are mostly in a 1:1 ratio. Therefore, it is believed to be the binding and inactivation of ceramide by I2PP2A that liberates the active form of PP2A, which, in turn, acts upon c-Myc, leading to the dephosphorylation and degradation. In cancer cells, elevated levels of I2PP2A were observed, which inhibits most of the available PP2A and results in stable (active) oncogenic c-Myc. The stable form of c-Myc can mediate tumor growth and cancer progression by upregulating expression of several oncogenes. I2PP2A: Protein phosphatase 2A inhibitor 2; PP2A: Protein phosphatase 2A.
Figure 5
Figure 5. Sphingosine kinase/sphingosine-1-phosphate-mediated regulation of cellular functions
Several growth factors and interleukins can activate SK by phosphorylation. Following activation, SK can translocate to the plasma membrane, where it phosporylates sphingosine to S1P. S1P is a bioactive lipid molecule, which can function as an intracellular messenger or is secreted out of the cell and coupled to its G-protein-coupled receptors (S1PRs) to mediate prosurvival, cell proliferation, tumor growth and/or metastasis. PLD: Phospholipase D; S1P: Sphingosine-1-phosphate; S1PR: Sphingosine-1-phosphate receptor; SK: Sphingosine kinase.
Figure 6
Figure 6. Ceramide/sphingsine-1-phosphate rheostat in cancer and treatment
In pathological conditions such as cancer, decreased levels of ceramide and elevated levels of its metabolite S1P were observed, which favors inhibition of programmed cell death, induction of metastasis and drug resistance. Upon treatment, ceramide levels increase and S1P levels decrease. These changes regulate apoptosis, ER stress and/or autophagic cell death. ER: Endoplasmic reticulum; S1P: Sphingosine-1-phosphate.
Figure 7
Figure 7. Sphingosine kinase/sphingosine-1-phosphate-mediated imantinib resistance of chronic myeloid leukemia cells
The overexpression of SK1 in Bcr–Abl-positive cells leads to alteration of the levels of S1P and ceramide, which induces the stabilization/activation of Bcr–Abl, leading to the inhibition of apoptosis and drug resistance in chronic myeloid leukemia. KO: Knockout; S1P: Sphingosine-1-phosphate; SK: Sphingosine kinase; SPH: Sphingosine.

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