Bioactive Sphingolipids in Neuroblastoma

Rahmaniyan, Mehrdad; Qudeimat, Amr; Kraveka, Jacqueline M.

doi:10.5772/27830

Cited by 6 publications

(7 citation statements)

References 169 publications

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“…Since VEGF is highly overexpressed in poor prognosis neuroblastoma, SphK2 overexpression and S1P generation could potentially promote neuroblastoma progression [36]. S1P also appaB, AKT/PI3K, and STAT3 [38]. Li et al reported that FTY720, a sphingosine analogue and S1P receptor modulatory agent, exerts an antitumor effect on neuroblastoma cells by reducing SphK2 expression, thereby increasing sphingosine levels and inducing apoptosis in a caspase-independent manner [39].…”

Section: Discussionmentioning

confidence: 99%

“…Li et al reported that FTY720, a sphingosine analogue and S1P receptor modulatory agent, exerts an antitumor effect on neuroblastoma cells by reducing SphK2 expression, thereby increasing sphingosine levels and inducing apoptosis in a caspase-independent manner [39]. Sphingosine and S1P have been reported to induce neuronal cell differentiation in neuroblastoma cells [38, 40]. Similar to sphingosine and S1P, ceramide induces neuronal cell differentiation via a mechanism mediated by PP2A [38].…”

Section: Discussionmentioning

confidence: 99%

“…Sphingosine and S1P have been reported to induce neuronal cell differentiation in neuroblastoma cells [38, 40]. Similar to sphingosine and S1P, ceramide induces neuronal cell differentiation via a mechanism mediated by PP2A [38]. Given that current neuroblastoma therapy aims at achieving tumor regression through cell differentiation, these findings may prove to be significant.…”

Section: Discussionmentioning

confidence: 99%

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Sphingadienes show therapeutic efficacy in neuroblastoma in vitro and in vivo by targeting the AKT signaling pathway

et al. 2018

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Neuroblastoma is a childhood malignancy that accounts for approximately 15% of childhood cancer deaths. Only 20–35% of children with metastatic neuroblastoma survive with standard therapy. Identification of more effective therapies is essential to improving the outcome of children with high-stage disease. Sphingadienes (SD) are growth-inhibitory sphingolipids found in natural sources including soy. They exhibit chemopreventive activity in mouse models of colon cancer, where they mediate cytotoxicity by inhibiting key pro-carcinogenic signaling pathways. In this study, the effect of SD on neuroblastoma was analyzed. Low micromolar concentrations of SD were cytotoxic to transformed and primary neuroblastoma cells independently of N-Myc amplification status. SD induced both caspase-dependent apoptosis and autophagy in neuroblastoma cells. However, only inhibition of caspase-dependent apoptosis protected neuroblastoma cells from SD-mediated cytotoxicity. SD also inhibited AKT activation in neuroblastoma cells as shown by reduced phosphorylated AKT levels. Pre-treatment with insulin attenuated SD-mediated cytotoxicity in vitro. SD-loaded nanoparticles (NP) administered parenterally to immunodeficient mice carrying neuroblastoma xenografts resulted in cytotoxic levels of SD in the circulation and significantly reduced tumor growth compared to vehicle-treated controls. Analysis of tumor extracts demonstrated reduced AKT activation in tumors of mice treated with SD-NP compared to controls treated with empty NP. Our findings indicate SD are novel potential chemotherapeutic agents that promote neuroblastoma cell death and reduce tumorigenicity in vivo.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Sphingadienes show therapeutic efficacy in neuroblastoma in vitro and in vivo by targeting the AKT signaling pathway

et al. 2018

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“…Ceramide can be cytotoxic and acts as a suppressor of a tumor phenotype. Therefore, cancer cells evolve mechanisms to escape from the sphingolipidmediated cell death [54]. However, no data on levels of ceramide or other active lipids, e.g., dihydroceramide, glucosylceramide or sphingosine 1-phosphate, and enzymes involved in their metabolism, were yet reported for cancer cells targeted with ganglioside-specific antibodies.…”

Section: Analysis Of Signaling Pathways Induced By Targeting Of Ganglmentioning

confidence: 97%

Targeting of tumor-associated gangliosides with antibodies affects signaling pathways and leads to cell death including apoptosis

Horwacik

Rokita

2015

Apoptosis

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Gangliosides are a diverse group of sialic acid containing glycosphigolipids that are abundantly present in an outer plasma membrane of some cells. Biological roles of gangliosides and other lipids in cell fate regulation are being extensively studied. Gangliosides are well known to be involved in interactions between cells and in signal transduction to regulate growth, adhesion and motility. Moreover, many gangliosides are tumor-associated antigens over-expressed on several tumor types. As a result, monoclonal antibodies binding gangliosides can be used to diagnose, monitor and to treat cancer patients. In the review, we gather and discuss data of various research groups on direct cytotoxic effects elicited by several ganglioside-specific antibodies, which bind to GM2, N-acetyl-GM2, N-glycolyl-GM2, GM3, GD3, GD2, O-acetyl-GD2, without involvement of immunological mechanisms. Thus, in cultures of numerous human and mouse cancer cell lines, the antibodies were reported to cause morphological changes, aggregation and detachment of cells, inhibition of proliferation and cell death involving necrosis, apoptosis and oncosis-like mechanisms. Additionally, data on proteome alterations were reviewed that encompass, among others, changes in kinome (P38, JNK, c-MET, ERK1/2, PI3K, AKT, FAK, aurora A, B, C), protein levels of transcription factors (P53, MYCN, HSF1) and pro-apoptotic proteins (caspase 3, BAX). Next, we collected data on application of the antibodies to enhance cytotoxicity of chemotherapeutic drugs and small molecule inhibitors. Finally, further research perspectives on the topic are discussed.

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“…Specified premigratory neural crest cells exhibit epithelial characteristics and enter EMT under temporal control by a well-characterized gene regulatory network to adopt a migratory, mesenchymal physiology 17,19 , making it an excellent model to test how membrane lipid changes facilitate the transition to a mesenchymal fate. Evidence from the neural crest-derived pediatric cancer, neuroblastoma, suggests that lipid metabolism plays a critical role in neural crest biology 20,21 . In neuroblastoma, receptor tyrosine kinase activation is mediated by the organization of Src kinases into ordered plasma membrane microdomains 20 .…”

Section: Introductionmentioning

confidence: 99%

Temporal changes in plasma membrane lipid content induce endocytosis to regulate developmental epithelial-to-mesenchymal transition

Piacentino

Hutchins

Andrews

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Epithelial-to-mesenchymal transition (EMT) is a dramatic change in cellular physiology during development and metastasis, which requires coordination between cell signaling, adhesion, and membrane protrusions. These processes all involve dynamic changes in the plasma membrane; yet, how membrane lipid content regulates membrane function during EMT remains incompletely understood. By screening for differential expression of lipid-modifying genes over the course of EMT in the avian neural crest, we have identified the ceramide-producing enzyme neutral sphingomyelinase 2 (nSMase2) as a critical regulator of a developmental EMT. nSMase2 expression begins at the onset of EMT, and in vivo knockdown experiments demonstrate that nSMase2 is necessary for neural crest migration. We find that nSMase2 promotes Wnt and BMP signaling and is required to activate the mesenchymal gene expression program. Mechanistically, we show that nSMase2-dependent ceramide production is necessary for and sufficient to up-regulate endocytosis and is required for Wnt co-receptor internalization. Finally, inhibition of endocytosis in the neural crest mimics the loss of migration and Wnt signaling observed following nSMase2 knockdown. Our results support a model in which nSMase2 is expressed at the onset of neural crest EMT to produce ceramide and facilitate receptor-mediated endocytosis of Wnt and BMP signaling complexes, thereby activating promigratory gene expression. These results highlight the critical role of plasma membrane lipid metabolism in regulating transcriptional changes during developmental EMT programs.

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Bioactive Sphingolipids in Neuroblastoma

Cited by 6 publications

References 169 publications

Sphingadienes show therapeutic efficacy in neuroblastoma in vitro and in vivo by targeting the AKT signaling pathway

Sphingadienes show therapeutic efficacy in neuroblastoma in vitro and in vivo by targeting the AKT signaling pathway

Targeting of tumor-associated gangliosides with antibodies affects signaling pathways and leads to cell death including apoptosis

Temporal changes in plasma membrane lipid content induce endocytosis to regulate developmental epithelial-to-mesenchymal transition

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