Chapter Two - Diverse Functions of Ceramide in Cancer Cell Death and Proliferation

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Abstract

Ceramide, a bioactive sphingolipid, is now at the forefront of cancer research. Classically, ceramide is thought to induce death, growth inhibition, and senescence in cancer cells. However, it is now clear that this simple picture of ceramide no longer holds true. Recent studies suggest that there are diverse functions of endogenously generated ceramides, which seem to be context dependent, regulated by subcellular/membrane localization and presence/absence of direct targets of these lipid molecules. For example, different fatty-acid chain lengths of ceramide, such as C16-ceramide that can be generated by ceramide synthase 6 (CerS6), have been implicated in cancer cell proliferation, whereas CerS1-generated C18-ceramide mediates cell death. The dichotomy of ceramides’ function in cancer cells makes some of the metabolic enzymes of ceramide synthesis potential drug targets (such as Cers6) to prevent cancer growth in breast and head and neck cancers. Conversely, activation of CerS1 could be a new therapeutic option for the development of novel strategies against lung and head and neck cancers. This chapter focuses on recent discoveries about the mechanistic details of mainly de novo-generated ceramides and their signaling functions in cancer pathogenesis, and about how these mechanistic information can be translated into clinically relevant therapeutic options for the treatment of cancer.

Section snippets

Structure and Metabolism of Ceramide

Bioactive sphingolipid ceramide can be synthesized through multiple different pathways within the cell. Ceramide is composed of a sphingosine backbone, which is amide-linked to a fatty acyl chain, varying in length from C14 to C26 (Fig. 2.1) (Ogretmen and Hannun, 2004, Ponnusamy et al., 2010). Ceramide serves as a structural precursor for complex sphingolipids, such as sphingomyelin (SM), ceramide-1-phosphate (C1P), or glucosylceramide (GlcCer) and galactosylceramide (GalCer), and precursors

Distinct Functions of CerS1–6

Recent studies indicate that different fatty-acid chain lengths of ceramide may have different functions in cancer pathogenesis, highlighting the importance of ceramide synthases (CerS) in sphingolipid metabolism. CerS, identified as the yeast longevity assurance gene 1 (LAG1), is known to regulate life span/longevity in Saccharomyces cerevisiae, and its deletion prolongs the replicative lifespan of yeast (Guillas et al., 2001, Jazwinski and Conzelmann, 2002). Within Caenorhabditis elegans,

Novel Ceramide–Protein Interactions that Regulate Ceramide Metabolism and Signaling

Diverse and distinct functions of ceramides can be partially explained by the discovery of novel ceramide–protein interactions (Table 2.1). One of the recently identified proteins known to bind to ceramide is CERT. CERT specifically transports ceramide from the ER to the trans-Golgi for SM synthesis (Hanada et al., 2003, Hanada et al., 2009). The crystal structure of CERT suggests that ceramide binds within the hydrophobic core of the protein for transport (Hanada et al., 2003, Hanada et al.,

Clinical Relevance of Ceramide Metabolism and Signaling in Cancer Pathogenesis, Therapy, or Drug Resistance

Recent studies suggest that ceramide has important clinical significance in cancer pathogenesis and prognosis (Fig. 2.3). In 2004, data from our laboratory showed that total ceramide levels were elevated in the majority of HNSCC tissues compared with noncancerous adjacent head and neck tissues (Karahatay et al., 2007). Interestingly, only C18-ceramide, and not other ceramide species, was significantly lower in ∼ 70% of the tumor tissues of HNSCC patients sampled, when compared to controls, and

Ceramide/Sphingosine-Based Anticancer Therapeutics

Pro-cell death function of ceramide suggests that ceramide mimetics or analogues may open doors to new therapies to battle cancer (Table 2.2). Thus, finding ways to increase ceramide either by exogenous treatment or by elevating endogenous ceramide in cancer cells is desired. Conversely, S1P has been shown to promote cancer pathogenesis; thus, suppression of its generation/accumulation could suppress tumor growth as an alternative treatment strategy.

One common approach to promote apoptosis in

Conclusions

Over the past two decades, the field of sphingolipid research has expanded immensely. The importance of sphingolipids, in particular ceramide, is well established in cancer. Previously, ceramide was classified as a “pro-cell death molecule”; however, it is now evident that not all ceramides are created equally, and that ceramides with different fatty-acid chain lengths exhibit distinct biological functions in a context-dependent manner. Although mechanisms that regulate distinct functions of

Acknowledgments

This work was supported by research grants CA088932, DE016572, and CA097132 to B. O. S. A. S was supported by funds from Wachovia Foundation and Abney Foundation, and NIH F30 ES019464.

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