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Journal ArticleDOI

Ceramide-orchestrated signalling in cancer cells

01 Jan 2013-Nature Reviews Cancer (Nature Publishing Group)-Vol. 13, Iss: 1, pp 51-65
TL;DR: This Review focuses on ceramide signalling and the targeting of specific metabolic junctures to amplify the tumour suppressive activities of ceramide.
Abstract: One crucial barrier to progress in the treatment of cancer has been the inability to control the balance between cell proliferation and apoptosis: enter ceramide. Discoveries over the past 15 years have elevated this sphingolipid to the lofty position of a regulator of cell fate. Ceramide, it turns out, is a powerful tumour suppressor, potentiating signalling events that drive apoptosis, autophagic responses and cell cycle arrest. However, defects in ceramide generation and metabolism in cancer cells contribute to tumour cell survival and resistance to chemotherapy. This Review focuses on ceramide signalling and the targeting of specific metabolic junctures to amplify the tumour suppressive activities of ceramide. The potential of ceramide-based therapeutics in the treatment of cancer is also discussed.
Citations
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Journal ArticleDOI
TL;DR: These results highlight critical roles for bioactive sphingolipids in most, if not all, major cell biological responses, including all major cell signalling pathways, and they link sphingoipid metabolism to key human diseases.
Abstract: Studies of bioactive lipids in general and sphingolipids in particular have intensified over the past several years, revealing an unprecedented and unanticipated complexity of the lipidome and its many functions, which rivals, if not exceeds, that of the genome or proteome. These results highlight critical roles for bioactive sphingolipids in most, if not all, major cell biological responses, including all major cell signalling pathways, and they link sphingolipid metabolism to key human diseases. Nevertheless, the fairly nascent field of bioactive sphingolipids still faces challenges in its biochemical and molecular underpinnings, including defining the molecular mechanisms of pathway and enzyme regulation, the study of lipid-protein interactions and the development of cellular probes, suitable biomarkers and therapeutic approaches.

1,025 citations

Journal ArticleDOI
TL;DR: Recording from subjects selectively listening to one of two competing speakers using magnetoencephalography indicates that concurrent auditory objects, even if spectrotemporally overlapping and not resolvable at the auditory periphery, are neurally encoded individually in auditory cortex and emerge as fundamental representational units for top-down attentional modulation and bottom-up neural adaptation.
Abstract: A visual scene is perceived in terms of visual objects. Similar ideas have been proposed for the analogous case of auditory scene analysis, although their hypothesized neural underpinnings have not yet been established. Here, we address this question by recording from subjects selectively listening to one of two competing speakers, either of different or the same sex, using magnetoencephalography. Individual neural representations are seen for the speech of the two speakers, with each being selectively phase locked to the rhythm of the corresponding speech stream and from which can be exclusively reconstructed the temporal envelope of that speech stream. The neural representation of the attended speech dominates responses (with latency near 100 ms) in posterior auditory cortex. Furthermore, when the intensity of the attended and background speakers is separately varied over an 8-dB range, the neural representation of the attended speech adapts only to the intensity of that speaker but not to the intensity of the background speaker, suggesting an object-level intensity gain control. In summary, these results indicate that concurrent auditory objects, even if spectrotemporally overlapping and not resolvable at the auditory periphery, are neurally encoded individually in auditory cortex and emerge as fundamental representational units for top-down attentional modulation and bottom-up neural adaptation.

696 citations

Journal ArticleDOI
TL;DR: The interdependencies of mTOR signalling and metabolism pathways in cancer and how metabolic reprogramming in response to changes in m TOR signalling and vice versa can sustain tumorigenicity are discussed.
Abstract: Oncogenic signalling and metabolic alterations are interrelated in cancer cells. mTOR, which is frequently activated in cancer, controls cell growth and metabolism. mTOR signalling regulates amino acid, glucose, nucleotide, fatty acid and lipid metabolism. Conversely, metabolic inputs, such as amino acids, activate mTOR. In this Review, we discuss how mTOR signalling rewires cancer cell metabolism and delineate how changes in metabolism, in turn, sustain mTOR signalling and tumorigenicity. Several drugs are being developed to perturb cancer cell metabolism. However, their efficacy as stand-alone therapies, similar to mTOR inhibitors, is limited. Here, we discuss how the interdependence of mTOR signalling and metabolism can be exploited for cancer therapy.

587 citations

Journal ArticleDOI
TL;DR: The role of aberrant lipid biosynthesis in cancer cell migration and invasion, and in the induction of tumour angiogenesis, is explored.
Abstract: An increased rate of lipid synthesis in cancerous tissues has long been recognised as an important aspect of the rewired metabolism of transformed cells. However, the contribution of lipids to cellular transformation, tumour development and tumour progression, as well as their potential role in facilitating the spread of cancerous cells to secondary sites, are not yet fully understood. In this article, we review the recent findings that support the importance of lipid synthesis and metabolism in tumorigenesis. Specifically, we explore the role of aberrant lipid biosynthesis in cancer cell migration and invasion, and in the induction of tumour angiogenesis. These processes are crucial for the dissemination of tumour cells and formation of metastases, which constitute the main cause of cancer mortality.

561 citations


Cites background from "Ceramide-orchestrated signalling in..."

  • ...PGE2) and phosphoinositides have important signalling functions in cells and tissues (Morad and Cabot, 2013; Wymann and Schneiter, 2008)....

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  • ...Furthermore, sphingolipids, such as ceramide or sphingosine-1-phosphate, eicosanoids (e.g. PGE2) and phosphoinositides have important signalling functions in cells and tissues (Morad and Cabot, 2013; Wymann and Schneiter, 2008)....

    [...]

  • ...Enzymes within the sphingolipid metabolism pathway are frequently deregulated in cancer, resulting in lower ceramide levels, which could cause resistance to chemotherapeutic treatment (see Morad and Cabot, 2013; and references therein)....

    [...]

  • ...In contrast, sphingosine-1phosphate (S1P) (produced from sphingosine by the action of sphingosine kinases) promotes cell proliferation, migration and angiogenesis (Morad and Cabot, 2013)....

    [...]

Journal ArticleDOI
Rachel Wilson1
TL;DR: This review summarizes the neurophysiology of the first two layers of this system: the peripheral olfactory receptor neurons and their postsynaptic targets in the antennal lobe and suggests some general principles with broad relevance to early sensory processing in other modalities.
Abstract: In the olfactory system of Drosophila melanogaster, it is relatively straightforward to target in vivo measurements of neural activity to specific processing channels. This, together with the numerical simplicity of the Drosophila olfactory system, has produced rapid gains in our understanding of Drosophila olfaction. This review summarizes the neurophysiology of the first two layers of this system: the peripheral olfactory receptor neurons and their postsynaptic targets in the antennal lobe. We now understand in some detail the cellular and synaptic mechanisms that shape odor representations in these neurons. Together, these mechanisms imply that interesting neural adaptations to environmental statistics have occurred. These mechanisms also place some fundamental constraints on early sensory processing that pose challenges for higher brain regions. These findings suggest some general principles with broad relevance to early sensory processing in other modalities.

328 citations

References
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Journal ArticleDOI
TL;DR: A molecular mechanism for regulation of the mammalian autophagy-initiating kinase Ulk1, a homologue of yeast ATG1, is demonstrated and a signalling mechanism for UlK1 regulation and autophagic induction in response to nutrient signalling is revealed.
Abstract: Autophagy is a process by which components of the cell are degraded to maintain essential activity and viability in response to nutrient limitation. Extensive genetic studies have shown that the yeast ATG1 kinase has an essential role in autophagy induction. Furthermore, autophagy is promoted by AMP activated protein kinase (AMPK), which is a key energy sensor and regulates cellular metabolism to maintain energy homeostasis. Conversely, autophagy is inhibited by the mammalian target of rapamycin (mTOR), a central cell-growth regulator that integrates growth factor and nutrient signals. Here we demonstrate a molecular mechanism for regulation of the mammalian autophagy-initiating kinase Ulk1, a homologue of yeast ATG1. Under glucose starvation, AMPK promotes autophagy by directly activating Ulk1 through phosphorylation of Ser 317 and Ser 777. Under nutrient sufficiency, high mTOR activity prevents Ulk1 activation by phosphorylating Ulk1 Ser 757 and disrupting the interaction between Ulk1 and AMPK. This coordinated phosphorylation is important for Ulk1 in autophagy induction. Our study has revealed a signalling mechanism for Ulk1 regulation and autophagy induction in response to nutrient signalling.

5,314 citations

Journal ArticleDOI
25 Jan 2002-Cell
TL;DR: Understanding the molecular events that contribute to drug-induced apoptosis, and how tumors evade apoptotic death, provides a paradigm to explain the relationship between cancer genetics and treatment sensitivity and should enable a more rational approach to anticancer drug design and therapy.

2,281 citations

Journal ArticleDOI
TL;DR: FoxO3 controls the two major systems of protein breakdown in skeletal muscle, the ubiquitin-proteasomal and autophagic/lysosomal pathways, independently and is pointed to as potential therapeutic targets in muscle wasting disorders and other degenerative and neoplastic diseases in which autophagy is involved.

1,747 citations

Journal ArticleDOI
TL;DR: The mitochondrial metabolism of cancer cells is deregulated owing to the use of glycolytic intermediates, which are normally destined for oxidative phosphorylation, in anabolic reactions and activation of the cell death machinery by stimulating mitochondrial membrane permeabilization could therefore be promising therapeutic approaches.
Abstract: Mitochondria are the cells' powerhouse, but also their suicidal weapon store. Dozens of lethal signal transduction pathways converge on mitochondria to cause the permeabilization of the mitochondrial outer membrane, leading to the cytosolic release of pro-apoptotic proteins and to the impairment of the bioenergetic functions of mitochondria. The mitochondrial metabolism of cancer cells is deregulated owing to the use of glycolytic intermediates, which are normally destined for oxidative phosphorylation, in anabolic reactions. Activation of the cell death machinery in cancer cells by inhibiting tumour-specific alterations of the mitochondrial metabolism or by stimulating mitochondrial membrane permeabilization could therefore be promising therapeutic approaches.

1,458 citations

Journal ArticleDOI
TL;DR: This work has shown that ceramide — a central molecule in sphingolipid metabolism — in effect functions as a tumour-suppressor lipid, inducing antiproliferative and apoptotic responses in various cancer cells, and that S1P induces responses that, on aggregate, render S 1P a tumours-promoting lipid.
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.

1,194 citations