ReviewLead genetic studies in Dictyostelium discoideum and translational studies in human cells demonstrate that sphingolipids are key regulators of sensitivity to cisplatin and other anticancer drugs
Section snippets
Introduction: chemotherapy and cancer
Of the roughly 1.5 million people diagnosed with cancer in the United States this year, many will receive chemotherapy at some time during the course of their treatment [1]. Conventional chemotherapy generally consists of the systemic administration of one or more cytotoxic drugs that are known to kill the rapidly dividing cancer cells. Despite its widespread use, conventional chemotherapy suffers from significant problems including lack of specificity towards the tumors (compared to normal
Dictyostelium discoideum: its biochemistry, cell biology and genetics make it a good target for drugs and understanding drug resistance
The simple eukaryote D. discoideum has been studied extensively since its discovery in 1935 [5] as a model for multicellular morphogenesis and cytodifferentiation using a combination of genetic, biochemical and molecular methods. It has an interesting life cycle, in which cells divide mitotically and remain single until they deplete their nutrient supply, at which time they aggregate using chemotaxis into multicellular assemblies (tissues) each consisting of 105 cells. The multicellular
Selecting drug resistant mutants
The drug cisplatin (cis-diamminedichloroplatinum (II)) is widely used to treat non-Hodgkin's lymphoma, small cell and non-small cell lung, testicular, ovarian, head and neck, esophageal, and bladder cancer [26]. It is a small molecular weight molecule that primarily forms covalent adducts with adjacent purines on DNA [27]. Its anticancer effect is widely believed to be due to this chemistry, although there is a generally poor understanding of the subsequent signaling pathways that regulate its
Sphingolipid metabolism – development, cell motility, and drug sensitivity
Three of the genes identified in the mutant screen for cisplatin resistance were of particular interest. The regA cAMP phosphodiesterase had been studied. Its role in development and its regulation of protein kinase A (PKA) were well established [34] and PKA was previously linked to cisplatin resistance in CHO cells [35]. Additional work on PKA mutants in D. discoideum was done to show that cisplatin resistance was indeed PKA dependent (unpublished). Golvesin has been shown to be a Golgi
Validation of the role of S-1-P lyase and sphingosine kinase in human cells – extending the paradigm
As demonstrated above, model systems with powerful genetics are critical to identifying novel information about important biomedical problems such as the molecular basis of cisplatin resistance. Not only can un-biased genetic selections/screens be done, but further validation and mechanistic interrogation can be done rapidly and with little expense. However, these new ideas must be translated to human systems, allowing the verification of their importance to human health and physiology.
The
Ceramide synthase enzymes
Further studies have looked at the role of the other bioactive sphingolipid, ceramide, in determining cellular sensitivity to drugs. The guiding idea here was that if increased levels of S-1-P result in decreased sensitivity, then increased levels of ceramide would be expected to increase sensitivity. Moreover, this would provide an opportunity to test directly the S-1-P/ceramide rheostat model with respect to drug sensitivity. Indeed, there were reports that exogenously added soluble membrane
The future
Extensive genetic and pharmacological investigations in D. discoideum and human cells have shown that sphingolipids, and the enzymes that regulate their homeostasis, play a central role in controlling the response of a cell to specific chemotherapeutic drugs. The D. discoideum system allowed the initial blind selection of mutants, and a rapid way of making additional isogenic mutants and testing the overall hypothesis that modulating the activity of the S-1-P metabolizing enzymes could
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Simple system - substantial share: The use of Dictyostelium in cell biology and molecular medicine
2013, European Journal of Cell BiologyCitation Excerpt :The finding could explain the higher susceptibility of human patients with mitochondrial disease to recurrent bacterial infections (Edmonds, 2004). Dictyostelium is also being used for pharmacological research in order to investigate the action of mood-stabilizing drugs such as lithium or valproic acid that are widely used to treat bipolar disorder and epilepsy (Chang et al., 2011; Ludtmann et al., 2011; Terbach et al., 2011; Williams et al., 2002), or of chemotherapeutic drugs employed in anti-cancer treatment (Alexander and Alexander, 2011). This list could be further extended by a number of interesting studies ranging from the investigation of the pathological processes underlying lissencephaly (Rehberg et al., 2005), and the cell biology and molecular base of lysosomal and trafficking diseases (Maniak, 2011), to the misregulation of the actin cytoskeleton causing a variety of disease pathologies, including compromised immunity, neurodegeneration, and cancer spread (Carnell and Insall, 2011).
S1P lyase in skeletal muscle regeneration and satellite cell activation: Exposing the hidden lyase
2013, Biochimica et Biophysica Acta - Molecular and Cell Biology of LipidsEvolution and Diversity of Dictyostelid Social Amoebae
2012, ProtistCitation Excerpt :Moreover, certain human mitochondrial diseases are being addressed using D. discoideum, such as a signaling pathway regulated by the AMP-activated protein kinase (AMPK) that has been involved in the underlying cytopathological symptoms (Carilla-Latorre et al. 2010; Francione et al. 2011). D. discoideum has also proved useful in pharmacogenomics as a model for studying the mechanisms of action of drugs such as the chemotherapeutic drug cisplatin and the mood-stabilizing drugs valproic acid and lithium (Alexander and Alexander 2011; Ludtmann et al. 2011). The first completed dictyostelid genome sequence was that of D. discoideum, published in 2005 (Eichinger et al. 2005).
Cell-derived microvesicles and antitumoral multidrug resistance
2012, Comptes Rendus - BiologiesCitation Excerpt :This could sign a way of propagating multidrug resistance both in vitro and in vivo, as already observed in the vesicle-mediated propagation of a few tumors [24]. D. discoideum has already shown its interest as a model for human disease [13–21]. It could as well be thought as a model for unraveling the mechanisms of multidrug resistance, still severely impairing the antitumoral chemotherapeutic treatments.
Truth and consequences of sphingosine-1-phosphate lyase
2012, Advances in Biological RegulationCitation Excerpt :This review will focus on recent insights related to SPL-mediated cell biology, the structure of prokaryotic and eukaryotic SPL proteins as revealed by crystallization, the function of SPL reaction products, the consequences of permanent SPL disruption in mice, and SPL targeting in several preclinical models of human diseases. For more information on the biochemical characteristics of SPL, its tissue distribution, transcriptional and post-transcriptional regulation, developmental functions, other aspects of SPL-mediated biology in human cells and metazoan model systems, and its important role in immune regulation, the reader is referred to several recent reviews (Alexander and Alexander, 2011; Bourquin et al., 2011; Gräler, 2010; Kumar and Saba, 2009; Serra and Saba, 2010; Van Veldhoven, 2000). In 2007, Soriano and colleagues published the first characterization of an SPL knockout mouse generated by a gene trap insertion mutagenesis screen (Schmahl et al., 2007).
A view on sphingolipids and disease
2011, Chemistry and Physics of LipidsCitation Excerpt :A group of drugs that lead to increased ceramide levels by inhibition of enzymes that use ceramide as a substrate, or by reduced ceramide consumption is available (Radin, 2001; Wennekes et al., 2009; Gangoiti et al., 2010) or under development (Gouazé-Andersson et al., 2011). Studies in Dictyostelium discoideum indicate that the activities of S1P-lyase, sphingosine kinase, and ceramide synthase also affect the survival of a cell in the presence of anticancer drugs like cis-platin (Alexander and Alexander, 2011). Even intake of dietary sphingolipids can have an impact on cancer progression (Duan and Nilsson, 2009), although the molecular details underlying the observations are largely unclear: for example, sphingomyelin consumption inhibits colon carcinogenesis (Schmelz et al., 1996), or glucosylceramide intake inhibits tumor growth of human head and neck squamous cell carcinoma in mice (Fujiwara et al., 2011).