Loss of the Ceramide Transfer Protein Augments EGF Receptor Signaling in Breast Cancer

Heering, Johanna; Weis, Nicole; Holeiter, Monika; Neugart, Felix; Staebler, Annette; Fehm, Tanja; Bischoff, Annabell; Schiller, Jürgen; Duss, Stephan; Schmid, Simone; Korte, Thomas; Herrmann, Andreas

doi:10.1158/0008-5472.can-11-3069

Cited by 38 publications

(35 citation statements)

References 47 publications

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“…In addition, TNBC are aggressive because of their frequent recurrence and high metastatic potential (37). Ceramide transfer protein (CERT) was recently reported to determine the signaling output of the EGF receptor (EGFR/ErbB1), which is upregulated in TNBC (38). Reduced expression of CERT in TNBC is associated with alterations in plasma membrane organization and PLD2 activation (38).…”

Section: Role Of Pld Up-regulated In Cancermentioning

confidence: 99%

“…Ceramide transfer protein (CERT) was recently reported to determine the signaling output of the EGF receptor (EGFR/ErbB1), which is upregulated in TNBC (38). Reduced expression of CERT in TNBC is associated with alterations in plasma membrane organization and PLD2 activation (38). Heering et al (38) suggested that the loss of CERT might trigger aberrant ligand-induced ErbB1 signaling through PLD2 activation, which may be relevant to the design of therapeutic interventions targeting TNBC.…”

Section: Role Of Pld Up-regulated In Cancermentioning

confidence: 99%

“…Reduced expression of CERT in TNBC is associated with alterations in plasma membrane organization and PLD2 activation (38). Heering et al (38) suggested that the loss of CERT might trigger aberrant ligand-induced ErbB1 signaling through PLD2 activation, which may be relevant to the design of therapeutic interventions targeting TNBC. Choline kinase-␣ (ChK-␣) is up-regulated in several cancers and a major contributor to increased phosphocholine, which is known as a metabolic hallmark in various cancers (39).…”

Section: Role Of Pld Up-regulated In Cancermentioning

confidence: 99%

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Functional Regulation of Phospholipase D Expression in Cancer and Inflammation

Kang

Choi

Min

2014

Journal of Biological Chemistry

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Phospholipase D (PLD) regulates downstream effectors by generating phosphatidic acid. Growing links of dysregulation of PLD to human disease have spurred interest in therapeutics that target its function. Aberrant PLD expression has been identified in multiple facets of complex pathological states, including cancer and inflammatory diseases. Thus, it is important to understand how the signaling network of PLD expression is regulated and contributes to progression of these diseases. Interestingly, small molecule PLD inhibitors can suppress PLD expression as well as enzymatic activity of PLD and have been shown to be effective in pathological mice models, suggesting the potential for use of PLD inhibitors as therapeutics against cancer and inflammation. Here, we summarize recent scientific developments regarding the regulation of PLD expression and its role in cancer and inflammatory processes.Phospholipase D produces phosphatidic acid (PA) 2 via hydrolysis of phospholipids such as phosphatidylcholine and cardiolipin. As a lipid second messenger, PA has been implicated in a wide range of pathophysiological processes including proliferation, oncogenesis, inflammation, phagocytosis, membrane fusion, and spermatogenesis. Phosphatidylcholine-specific PLD1 and PLD2 are the classic mammalian isoforms of PLD (1, 2). Growth factor, mitogen, and inflammatory cytokines up-regulate expression and activity of PLD; however, aberrant dysregulation of PLD occurs in various cancers and inflammation-related diseases. Accordingly, it is important to understand how expression of PLD is regulated and contributes to these diseases.An association between inflammation and cancer has been observed (3) and supported by recent epidemiological data that indicated ϳ20% of cancer deaths are linked to chronic infections and persistent inflammation (4). The PLD signaling pathway provides a possible molecular link between inflammation and cancer; however, systematic investigation of PLD as a therapeutic target has only begun within the last few years with the development of small molecule PLD inhibitors and PLD knock-out mice (5-13). This review covers recent advances in the regulation of PLD expression and its role in cancer and inflammation.

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Section: Role Of Pld Up-regulated In Cancermentioning

confidence: 99%

Section: Role Of Pld Up-regulated In Cancermentioning

confidence: 99%

Section: Role Of Pld Up-regulated In Cancermentioning

confidence: 99%

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Functional Regulation of Phospholipase D Expression in Cancer and Inflammation

Kang

Choi

Min

2014

Journal of Biological Chemistry

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“…Tumor cells are known to evade the immune system by downregulating complement activation (56). Interestingly, a recent study found downregulation of CERT in cancers refractory to treatment (57). Thus, the loss of CERT could be a mechanism by which tumor cells reduce complement activation, resulting in reduced clearance of tumor cells by the immune system.…”

Section: Discussionmentioning

confidence: 99%

Complement Activation by Ceramide Transporter Proteins

Bode

Losen

Buurman

et al. 2014

The Journal of Immunology

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C1q is the initiator of the classical complement pathway and, as such, is essential for efficient opsonization and clearance of pathogens, altered self-structures, and apoptotic cells. The ceramide transporter protein (CERT) and its longer splicing isoform CERTL are known to interact with extracellular matrix components, such as type IV collagen, and with the innate immune protein serum amyloid P. In this article, we report a novel function of CERT in the innate immune response. Both CERT isoforms, when immobilized, were found to bind the globular head region of C1q and to initiate the classical complement pathway, leading to activation of C4 and C3, as well as generation of the membrane attack complex C5b–9. In addition, C1q was shown to bind to endogenous CERTL on the surface of apoptotic cells. These results demonstrate the role of CERTs in innate immunity, especially in the clearance of apoptotic cells.

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“…Especially, in Immune system, all kinds of immunoglobulins are glycoproteins. It is reported that Cert expression decreases in Triple Negative Breast Cancer (TNBC), an aggressive cancer type in metastasis [7]. Consistent with the recent discovery [8]: Lipid rafts and its associated actin cytoskeleton contribute to the localization and function of ABC transporter, the marker of side population in flow cytometry, our unpublished data with head and neck Squamous cell carcinoma (HNSCC) suggest that hypoxia induces the characteristic of cancer stem cell, hormone and growth factor enhance hypoxic response of HNSCC, which are probably the reason of resistance to chemotherapy for cancers.…”

Section: Editorialmentioning

confidence: 99%

Targeting Lipid Rafts, Seeking Cures for Diseases

Wang¹

2015

SOJMID

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Open Access Editorialenvironmental risk factors to develop preventive medicine for leukemia.The components and ratio of lipids species assembled into biomembrane is another essential factor contributing to the specific behaviors of lipid rafts. From two lipid metabolism genes mutation models, we understood that the nature of biomembrane are very different between mammals and Drosophila. NeutralCeramidase (N-CDase) nude mice do not have significant phenotype, even the N-CDase nude MEFs only show around 10% weak cytotoxic toleration as compared to wild type MEFs by FACS analysis (unpublished data), whereas Drosophila N-CDase knockout is lethal [4]. In addition, the outcome of impairment of lipid metabolism and membrane organization affects profoundly different on survival and adaptation responses between mouse and fly: most of Ceramide Transfer Protein (Cert) nude mice die from organogenetic defects at the stage of embryo 11. 5 days without any significant changes in fluidity of membrane [5]. Interesting enough, Cert nude flies fully develop to adulthood with around 35% increase of fluidity of membrane, 33% and 40% increase of cellular glucose and modification proteins, respectively, which resulted in shorter lifespan to flies [6].The biological aging is the most risk factor for human diseases. The alteration of the lipid metabolism and cholesterol homeostasis contribute to cardiovascular diseases caused by aging of blood vessels, Alzheimer's disease character by neuron degeneration, and so on. Up to date, the most accepted events that are demonstrated to influence the aging process are energy metabolism: Caloric restriction, insulin pathways and electron transport chains, all mainly occur in mitochondria. In our Cert mutant mouse model, ceramide accumulation in ER results in mild ER adaption response to the stress, but severe mitochondria dysfunction. With the altered sphingolipids components in plasma membrane and organelles, developmental defects of heart in this Cert mutant mouse lead embryo to die from heart failure. As the primary researcher of the mouse model, I hypothesize that the biological aging process in cells due to dysfunction of mitochondria is the major cause of organogenetic failure in Cert null mice. Our next study will explore how lipid metabolism play a role in aging process with Cert mutant mouse model, we will develop and discover some compounds involved in lipid metabolism that may able to rescue the developmental defect of cardiovascular that have high morbidity in new births.

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Loss of the Ceramide Transfer Protein Augments EGF Receptor Signaling in Breast Cancer

Cited by 38 publications

References 47 publications

Functional Regulation of Phospholipase D Expression in Cancer and Inflammation

Functional Regulation of Phospholipase D Expression in Cancer and Inflammation

Complement Activation by Ceramide Transporter Proteins

Targeting Lipid Rafts, Seeking Cures for Diseases

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