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Therapeutic Implications of Ceramide-Regulated Signaling Cascades

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From “Bench to Bedside” is the often-used phrase that alludes to the potential clinical or therapeutic benefits of innovative basic science research or technologies. However, the “Bench to Bedside” phrase is often not supported by translationally-based research that exploits basic science discoveries. Based upon major leaps in our understanding of the biochemistry, biophysics and molecular biology of lipid-derived second messengers, the sphingolipid field is finally in position to embrace the “Bench to Beside” concept. This chapter will focus on studies that have begun to define the therapeutic potential of strategies that alter endogenous levels of ceramide or ceramide analogues in cardiovascular and cancer models. Wherever possible, results from translationally-based studies will be used to clarify or re-evaluate controversies in the literature.

The Bench—Ceramides and Signaling Cascades

The in vivo use of ceramide analogues, ceramide mimetics or agents that alter endogenous ceramide concentration can only be a reality after we fundamentally understand the mechanisms of action of ceramides on the multiplicity of redundant, interrelated signaling cascades that allow cells to communicate. It is now well established that ceramide interacts with multiple signaling cascades leading to cell growth arrest and/or apoptosis.1,2 Even though several candidate targets for ceramide have been suggested, including KSR,3 (see Chapter 7) PKCζ,4–8 MEKK1,7,9 PP2a,10 (see Chapter 6) VAV,11 PKR,12 cathepsin D13 and calpain,14 the ability of ceramide to directly bind to these intracellular signaling elements through a discrete ceramide-binding domain(s) has not been rigorously proven. Yet, a consensus of opinion is emerging, suggesting that ceramide interacts with multiple upstream elements in signaling cascades through generation and localization in discrete membrane microdomains.15–17

It can also be envisioned that ceramide ultimately acts as a cofactor, providing the specificity and selectivity necessary for multiple kinase interactions, leading to the formation of signaling complexes. Scaffold or anchoring proteins can regulate the interaction of multiple signaling elements to form these “signalosomes”.18–21 It is likely that lipid-derived second messengers, including ceramide, can augment these protein/protein interactions through specific lipid/protein interactions at discrete lipid-binding domains. In this way, ceramide can regulate the formation of unique, tissue-specific, signalosomes linked to growth regulation and apoptosis. In an analogous fashion, TNF “receptosomes” have been implicated as signaling vesicles, transmitting acid-SMase-generated ceramide and co-localized cathepsin from the endosome into the cytosol where it can access substrates.13

Our laboratory has recently reported three synergistic mechanisms by which ceramide can regulate signalosome formation in smooth muscle cell pericytes, and human embryonic kidney cells7,8,22 (Fig. 1). These signaling mechanisms are based upon earlier studies, from multiple investigators using various cell types, demonstrating that ceramide induces cell cycle arrest and/or apoptosis through simultaneous activation of stress-activating protein kinases (SAPK) and inhibition of extracellular signal regulated kinase (ERK) and /or AKT.23–32 However, the precise mechanism(s) by which ceramide concomitantly regulates these multiple signaling cascades has not been defined. Recent studies have suggested that interactions between ceramide and distinct PKC isotypes may be a unifying paradigm underscoring ceramide regulation of signalosomes. In the first mechanism, cell-permeable or physiological ceramides activate either immunoprecipitated or recombinant PKCζ, which induces formation of a MEKK1/SEK/SAPK signalosome.7 In a similar scenario, Wang et al have shown that PKCζ is a signaling intermediate for ceramide-activated SAPK in PC12 cells.26 In the second mechanism, ceramide competitively inhibits DAG-stimulated PKCϵ to disrupt the formation of a Raf/MEK/ERK signalosome, an event that is also associated with growth arrest.22 A third mechanism by which ceramide checks cell cycle progression is through a PKCζ-dependent, PI3K-independent inactivation of the pro-survival kinase, AKT.8 This mechanism also suggests that ceramide regulates binding interactions between PKCζ and upstream elements in the AKT cascade. These interactions are specific to individual PKC isotypes as ceramide induces PKCζ, but not PKCϵ, interactions with AKT. It is also possible that the actions of PKCζ to function as either an anti-mitogenic or pro-mitogenic kinase can be a consequence of specific lipid-derived second messengers (ceramide/PI3-lipids/arachidonate) that differentially couple PKCζ to either anti- or pro-mitogenic signalosomes.4,8,33 As we begin to manipulate endogenous levels of ceramide in pre-clinical models, confirmation of these signaling mechanisms in vivo will further elucidate their overall biological relevance.

Figure 1. Ceramide induces cell cycle arrest or apoptosis through multiple signal transduction cascades.

Figure 1

Ceramide induces cell cycle arrest or apoptosis through multiple signal transduction cascades.

The role of ceramide to interact with and differentially regulate PKC isotypes is still somewhat controversial. Multiple studies have shown that ceramide activates atypical PKCs, including PKCζ,4–8,26 while inactivating conventional or novel PKC isotypes.22,34–36 However, studies with photoaffinity-labeled ceramide were unable to reproduce these observations.37 Until we define the ceramide-binding domain(s) of individual PKC isotypes, we are left with the intriguing hypothesis of Van Blitterswijk,38 in which it was proposed that ceramide, but not diacylglycerol (DAG), binds to the unique single cysteine-rich domain (CRD) of PKCζ. In contrast, ceramide competes with DAG for either of the two CRD sites on conventional and novel PKC to inhibit activation. This hypothesis provides a plausible explanation for the Yin/Yang relationship observed between ceramide and DAG in terms of cell cycle progression.39 This may be analogous to the competitive interactions observed between ester- and ether-linked diglycerides40 as well as between arachidonate and ceramide4 for PKC isotypes. Understanding these specific lipid/protein interactions at both a molecular and biochemical level has the potential to allow future studies to translate these two-dimensional cell culture studies to three-dimensional in vivo models, in essence “kicking it up a notch”.

The Bedside—Ceramides and Cardiovascular Disease

The role of ceramides in the physiological and pathophysiological regulation of vascular smooth muscle function has been previously reviewed.41–45 Yet controversies still remain as to the exact role of ceramide in remodeling of atherosclerotic lesions or in hypertension. Translationally-based studies have been able to clarify some of these discrepancies. The role of ceramide as an anti-proliferative lipid in vivo is particularly well illustrated in studies by Johns et al, in which neutral SMase-generated ceramide formation is reduced in spontaneously hypertensive rats (SHR), contributing to increased VSMC proliferation.46 Even though ceramide, by itself, is an anti-proliferative metabolite, studies suggest that ceramide, as a component of oxidized low-density lipoproteins, contributes to the development of atherosclerotic lesions.47 Moreover, it has been suggested that SM-generated ceramide correlates with aggregated LDL particles.48 However, it is now believed that ceramide metabolites, including lactosylceramide and sphingosine-1-phosphate, are the ultimate mediators of oxidized LDL-induced VSM proliferation and differentiation.43,49 Alternatively, ceramide may be beneficial in limiting atherosclerosis through ceramide-dependent eNOS expression50 and inhibition of TNF-induced adhesion protein expression,51 subsequent to HDL binding to endothelial scavenger receptors. Ceramide also inhibits gene transcription of sterol regulatory element binding proteins to mediate a physiological feedback mechanism to lower cholesterol biosynthesis.52 Taken together, these studies directly illustrate some of the major difficulties in interpreting and rationalizing results between in vitro and in vivo models. Questions regarding multiple bioactive metabolites, subcellular localization, specific targets and intercalation into bilayers (bioavailability) may confound interpretations. For example, ambiguous results could be a result of divergent metabolic pathways leading to the formation of either pro-mitogenic (sphingosine-1-phosphate, lactosylceramide, galactosylceramide) or anti-mitogenic (sphingosine, sphinganine) metabolites.53–55 Furthermore, ceramide generation in the mitochondria56 as well as the nucleus,57 but not in the plasma membrane, may be critical events in apoptosis. Yet, two recent studies have documented the potential clinical utility of ceramides as anti-proliferative, vasodilatory or protective agents in arteries.58,59 Both of these studies take advantage of local, direct and acute delivery systems for cell-permeable ceramide analogues that are less likely to be metabolized than corresponding physiological ceramides.

In the first in vivo pre-clinical model, a cell-permeable ceramide analogue was delivered directly and acutely to the site of vascular injury. It was shown that C6-ceramide-coated balloon catheters prevent neointimal hyperplasia in rabbit carotid arteries58 (Fig. 2). The clinical correlate for such a model is restenosis after balloon angioplasty and/or stenting. Secondary occlusion of stented coronary arteries affects nearly 20% of the 1.5 million patients who undergo coronary angioplasty worldwide. The mechanism by which ceramide induces cell cycle arrest in stretch-injured vascular smooth muscle cells was mediated through inactivation of both ERK and AKT signaling cascades, validating in vitro findings.8,22,58 This study documents that intra-arterial drug delivery is technically feasible for cell-permeable lipids that target growth factor signaling cascades. Moreover, ceramide analogues or mimetics as adjuncts to polymer based coatings or as the coating themselves are uniquely suited to drug delivery platforms. These studies support future initiatives to locally and acutely deliver ceramide analogues as therapeutics to diminish proliferative pathologies. Innovative strategies to deliver ceramide analogues from various platforms, including stents or grafts, in proliferative smooth muscle pathologies such as restenosis after angioplasty, hemodialysis access failure, anastamoses or transjugular intrahepatic portosystemic shunting are currently under investigation.

Figure 2. Ceramide-coated balloon catheters limit neointimal hyperplasia after stretch injury in rabbit carotid arteries.

Figure 2

Ceramide-coated balloon catheters limit neointimal hyperplasia after stretch injury in rabbit carotid arteries. Top panels, H/E-stained carotid arteries, two weeks post-angioplasty. Bottom panels, Proliferating cell nuclear antigen expression in rabbit (more...)

In the second in vivo pre-clinical model, C8-ceramide was shown to significantly reduce focal cerebral ischemia in SHR rats.59 This study supports in vitro findings that have implicated TNF-generated ceramide in induction of tolerance to ischemia.60 It is speculated that ceramide-induced preconditioning protects cultured astrocytes against the proinflammatory effects of TNFα.61 In addition, this study alludes to the therapeutic applicability of intravenous or intracisternal infusion of cell-permeable ceramide analogues. In an analogous fashion, the ceramide mimetic, trimethylsphingosine, serves a protective role for myocardium and endothelium after ischemic/reperfusion injury.62 In addition, ceramide-activated KSR has been implicated as a compensatory pathway minimizing the pro-apoptotic and pro-inflammatory actions of TNF in irritable bowel disease patients.63 Taken together, these in vivo studies may help redefine ceramides as potential therapeutics with anti-proliferative and protective properties.

The putative clinical utility of ceramide analogues or related lipometics may rely on the differential effects ceramide has on multiple phenotypes in different tissues. We can speculate that ceramide functions as the ultimate “triple threat” to prevent restenosis or limit infarct size after ischemia by inducing vascular smooth muscle cell cycle arrest, maintaining wound-healing responses and diminishing the pro-inflammatory milieu. For example, C6-ceramide-coated balloon embolectomy catheters preferentially target dysfunctional, proliferative, vascular smooth muscle, inducing cell cycle arrest without inducing significant apoptosis or without diminishing the wound healing response.58 In fact, in unpublished data, we have shown that ceramide-coated catheters augment expression of endothelial cell-derived PDGF-ββ, supporting re-endothelialization and the potential to minimize pro-thrombogenic side effects of coated-stents. In addition, ceramide does not increase the expression of adhesion molecules in human vascular endothelial cells.64 Yet, in contrast to vascular smooth muscle, ceramide has been shown to activate pro-mitogenic cascades such as ras/ERK in fibroblasts,65 events consistent with wound healing responses. It is also plausible that exogenously delivered cell-permeable ceramides diminish recruitment of macrophage precursors to atherosclerotic or infracted lesions or vulnerable plaques. Supporting this contention are studies demonstrating that Fas ligand, which signals via ceramide, could diminish vessel inflammation by targeting macrophage/mononuclear cell infiltrates and not vascular endothelial cells.66,67,68 The ability of exogenous ceramide to diminish macrophage recruitment through apoptosis may be a result of inactivation of AKT signaling.69 Tissue-specific signaling cascades may be responsible for the orchestrated in vivo phenotype observed after local delivery of ceramide analogues.

In addition to ceramide's well-described role to inhibit cell cycle progression in airway smooth muscle,25 rat glomerular mesangial cells,24 A7r5 rat vascular smooth muscle cells8 as well as human coronary artery smooth muscle45, ceramide has also been implicated in vascular smooth muscle contractile responses. Ceramide has been shown to induce vasodilation of phenylephrine-contracted, endothelium-denuded, rat thoracic aortic rings.70,71 In contrast, ceramide has been reported to mediate contraction of rabbit rectosigmoid smooth muscle72,73 as well as inhibition of endothelium-dependent vasodilation in bovine coronary arteries.74 These discrepancies could be due to the role of an intact endothelial lining generating nitric oxide. Again data from local ceramide-delivery studies to limit infarct damage or stenosis58,59 may help clarify the discrepancies, arguing for a vasodilatory action of ceramide in vivo.

The Bedside—Ceramides and Cancer

The potential benefit of ceramide-based chemotherapy in cancer is based on the ability of exogenous short-chain ceramide analogues to induce apoptosis in transformed/cancer cell lines. To date, the exact mechanism(s) of ceramide-mediated cell signaling leading to apoptosis has not been clearly defined. Yet, many clinically important cytotoxic agents appear to be effective by synergizing with ceramide-mediated apoptotic signaling pathway in cancer cells. The cytotoxic effect of taxol is linked to the de novo synthesis of ceramide in MDA-MB 468 human breast cancer cells, and taxol-dependent cytotoxicity is abolished when ceramide formation is blocked using L-cycloserine, an inhibitor of de novo ceramide synthesis.75 Moreover, exogenous ceramide synergistically augmented taxol-induction of apoptosis.76 Doxorubicin also promotes ceramide formation and apoptosis in breast cancer cells.77 Tamoxifen has been shown to increase cellular ceramide levels by blocking conversion of ceramide to glucosylceramide, which was independent of estrogen receptor status.78,79 Furthermore, the combination of tamoxifen with agents, such as doxorubicin or cyclosporin A analogue, has been shown to exert synergistic effects on ceramide formation.80

Recent provocative pre-clinical studies by Schmelz et al suggest supplementing milk glycosphingolipids and C16 ceramide into animal diets can suppress colonic neoplasia by as much as 50%.81,82 In fact, it has been suggested that ceramides, as functional components of dairy foods and soybeans, can potentially lower colon carcinogenesis as well as lower cholesterol and LDL with elevation of HDL levels.83 Yet, the clinical utility of systemic delivery of exogenous ceramide may be limited by ceramide metabolism, again arguing for local delivery strategies. Ceramide can serve as a precursor for the synthesis of sphingosine-1-phosphate (S-1-P) and glucosylceramide (GlcCer), which are implicated in cancer cell growth. This metabolic conversion of ceramide into S-1-P and/or GlcCer may switch cancer cells from an apoptotic state to a cell growth state. Supporting this, the production of GlcCer from ceramide has been shown to prevent the induction of apoptosis and stimulate cancer cell growth.84,85 Additionally, studies show that S-1-P stimulates cell growth and inhibits apoptotic cell death by serving as both an extracellular regulator and an intracellular second messenger,86–89 indicating that targeting ceramidase or sphingosine kinase, which metabolize ceramide into mitogenic S-1-P, may be an effective treatment strategy against cancer. To this end, Novogen Inc. has begun clinical studies with a putative sphingosine kinase inhibitor.90 Other potential drug targets include inhibitors of ceramide hydrolysis, ceramide glucosylation, ceramide phosphorylation, and sphingosine phosphorylation. Additionally, activators of SM hydrolysis, glucosylceramide hydrolysis, de novo ceramide synthesis, S-1-P phosphohydrolysis, and Cer-1-P phosphohydrolysis could contribute to multi-drug-induced elevation of intracellular ceramide.

Interestingly, multi-drug resistant (MDR) cancers may be linked to augmented ceramide metabolism. Exposure to doxorubicin increases ceramide levels in drug-sensitive MCF-7 breast cancer cells, but not in the doxorubicin-resistant MCF-7-AdrR cells.77 Additionally, neither C6-Cer nor tamoxifen (a known inhibitor of GlcCer synthase) was cytotoxic alone, but the addition of tamoxifen to the C6-Cer treatment regimen decreased MCF-7-AdrR cell viability and elicited apoptosis. Further treatment of these cells with Adriamycin stimulated an increase in endogenous ceramide levels only if co-administered with tamoxifen, in which case augmented ceramide levels correlated with a further decline in cell viability. Since MCF-7-AdrR cells have a high level of GlcCer synthase activity, these cells may display resistance to exogenous cell-permeable ceramide as well as chemotherapeutic agents (i.e., doxorubicin and adriamycin) through metabolism of ceramide into GlcCer.

Studies in KB-V-1 MDR human epidermoid carcinoma cells also allude to the efficacy of augmenting endogenous ceramide levels in aggressive, MDR cancers. In these transformed cells, the multi-drug resistance modulator PSC 833 (a cyclosporin derivative) induced ceramide synthesis, which was blocked by fumonisin B1.91 Similar studies in KG1a cells, which are resistant to TNF-α and do not produce ceramide upon cytokine stimulation, can be sensitized by PSC 833, to restore ceramide generation by activation of neutral, but not acid, SMase activity.92 Additional evidence for inhibition of GlcCer synthesis as a potential target to augment endogenous ceramide levels and induce apoptosis comes from studies in a human neuro-epithelioma cell model.93 Although having no effect on cell viability when administered alone, GlcCer accumulation was fully suppressed by PDMP (D-threo-1-phenyl-2- decanoylamino-3-morpholino-1-propanol), significantly potentiating the apoptotic effect of C6-Cer. Thus, it is not surprising that targeting the GlcCer synthase with antisense cDNA or oligonucleotides reversed adriamycin-resistance in breast cancer cells.94 Taken together, these studies strongly suggest that targeted inhibition of ceramide metabolism potentiates cellular sensitivity to exogenous ceramide as well as other chemotherapeutic agents. This potentially translates to the use of lower doses of common anti-neoplastic drugs in ceramide-enhancing drug cocktails, as to synergistically induce cancer cell death with reduced overall side effects.

In addition to mediating some of the effects of cancer chemotherapy, ceramide has been implicated as the modulator of radiation therapy-induced cell death.95 Acid SMase-generated ceramide was shown to mediate radiation-induced apoptosis of micro-vascular and intestinal endothelial cells as well as lymphoid and haematopoitic cells.95,96 These events are critical for diminished tumor microvessel angiogenesis and subsequent diminished metastasis. These studies also suggest caution with brachytherapy (local irradiation) to inhibit restenosis, due to pro-thrombogenic complications of radiation-induced endothelial cell death. Supporting the “Yin/Yang” relationship between signaling lipids, S-1-P prevented radiation-induced ovarian damage, providing a novel therapeutic approach to preserve ovarian function in vivo.97 In a similar fashion, S-1-P has been shown to induce vasculogenesis and angiogenesis through activation of the EDG-1-receptor in vivo.98

The Bedside—Other Potential Applications for Ceramide-Based Therapeutics

Some of the initial in vivo applications of ceramide have been documented in cosmetology, with ceramide analogues and mimetics added to skin creams and shampoos.99,100 The rationales for these products are studies demonstrating that ceramide may induce keratinocyte cell death as well as augment barrier formation.101,102 Another novel in vivo application may be to target inositolphosphorylceramide formation in fungal infections. 103 Fungal pathogenesis in immuno-compromised patients is often life threatening. The formation of inositolphosphorylceramide analogues in fungi is essential for viability, suggesting inhibitors of IPC formation would make ideal antifungal drug candidates.103 It is even possible to contemplate ceramide-based therapeutic initiatives to limit viral infection, as fusion of HIV1 into the plasma membrane of CD4+ cells is dependent on the glycosphingolipids of membrane microdomains104

Targeting ceramide metabolism may also prove to be beneficial for diabetic patients. There is strong evidence that increased endogenous ceramide levels are associated with insulin resistance and the diabetic state. Studies, from as early as 1990, have shown that in the insulin-resistant state, intracellular concentrations of ceramide are elevated in rat skeletal muscle. 105 Ceramide analogues have also been shown to diminish insulin-induced glucose transport in cultured adipocytes.106,107 To begin identifying the mechanisms underlying ceramide-induced insulin resistance, ceramide has been shown to inhibit insulin-induced glucose transport by its inhibitory effect on AKT phosphorylation and GLUT4 translocation in 3T3-L1 adipocytes.108 This diminished AKT activity is a result of diminished AKT translocation and an augmented AKT phosphatase, independent of PI3kinase regulation.31 It is likely that ceramide metabolites also contribute to diabetic complications, as an increased accumulation of GlcCer has been observed in the kidneys of diabetic rats, which correlated with increased renal hypertrophy.109 Alternatively, glycosphingolipid formation may represent a significant pathway for glucose utilization in early diabetic nephropathy. In addition to diabetes, targeting ceramide metabolism to achieve fat reduction may be feasible, as ceramide blocks adipogenesis by decreasing the phosphorylation of C/EBP, a stress-activated transcriptional factor.110 In this model, inhibition of ceramide production reversed TNF-induced insulin resistance.110 In diseases of diminished leptin production, ceramide accumulation has been shown to induce apoptosis in lipid-laden pancreatic beta cells and skeletal muscle.111 Taken together, these studies suggest that dysfunctional ceramide metabolism may play a role in the diabetic state.

Conclusions—Back to the Bench

The failure of promising therapeutics in clinical trials underscores the complexity and redundancy of signaling cascades regulating cell growth or apoptosis. Thus, to be successful, translational research must be dependent upon basic scientific studies that define novel signaling targets for in vivo investigation and validation. The identification of ceramide-binding domains on putative targets should allow the formulation of even more specific or potent ceramide analogues or mimetics for study. It is truly the complementation of in vitro and in vivo studies that allow for the optimization of therapeutics that exploit these defined targets. As a case in point, targeted and local ceramide-based delivery methodologies are presently being optimized. The potential to incorporate anti-mitogenic ceramide analogues into conventional or cationic liposomal delivery systems may not only improve efficiency of transfer but also serve to augment gene transfer or oligonucleotide targeting therapies. These types of initiatives are only possible in an atmosphere of collaboration between basic and clinical scientists with combined skills in biophysics, molecular biology, pharmacology and bioengineering.

Acknowledgments

MK is supported by grants DK53715 and HL66371 from the National Institutes of Health and participates in a related project sponsored, in part, by MD3, Inc.

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