Ganglioside GD3 synthase (GD3S), a novel cancer drug target

Liu, Jinyi; Zheng, Xiangjin; Pang, Xu; Li, Li; Wang, Jinhua; Yang, Cui; Du, Guanhua

doi:10.1016/j.apsb.2018.07.009

Cited by 39 publications

(35 citation statements)

References 91 publications

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“…This sialyltransferase synthesizes the disialoganglioside GD3 [ 38 ], and the amount of GD3 was found to be reduced after IL-2 treatment. GD3 is mainly studied in tumor cells, because it is expressed at high levels in different tumor entities [ 39 ]. Nevertheless, GD3 is expressed on different immune cell types but at lower levels [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Sialylation of Human Natural Killer (NK) Cells Is Regulated by IL-2

Rosenstock

Bork

Massa

et al. 2020

JCM

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Sialic acids are terminal sugars on the cell surface that are found on all cell types including immune cells like natural killer (NK) cells. The attachment of sialic acids to different glycan structures is catalyzed by sialyltransferases in the Golgi. However, the expression pattern of sialyltransferases in NK cells and their expression after activation has not yet been analyzed. Therefore, the present study determines which sialyltransferases are expressed in human NK cells and if activation with IL-2 changes the sialylation of NK cells. The expression of sialyltransferases was analyzed in the three human NK cell lines NK-92, NKL, KHYG-1 and primary NK cells. NK-92 cells were cultured in the absence or presence of IL-2, and changes in the sialyltransferase expression were measured by qPCR. Furthermore, specific sialylation was investigated by flow cytometry. In addition, polySia and NCAM were measured by Western blot analyses. IL-2 leads to a reduced expression of ST8SIA1, ST6GAL1 and ST3GAL1. α-2,3-Sialylation remained unchanged, while α-2,6-sialylation was increased after IL-2 stimulation. Moreover, an increase in the amount of NCAM and polySia was observed in IL-2-activated NK cells, whereas GD3 ganglioside was decreased. In this study, all sialyltransferases that were expressed in NK cells could be identified. IL-2 regulates the expression of some sialyltransferases and leads to changes in the sialylation of NK cells.

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Section: Discussionmentioning

confidence: 99%

Sialylation of Human Natural Killer (NK) Cells Is Regulated by IL-2

Rosenstock

Bork

Massa

et al. 2020

JCM

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“…Many studies indicate that tumor-associated gangliosides are a result of initial oncogenic transformation and play a key role in tumor progression [ 24 ]. Accordingly, inhibition of GD2 and GD3 synthesis has been suggested as a therapeutic approach in several cancers [ 25 , 26 ]. However, methods to inhibit gangliosides in a clinical setting in the context of cancer are largely missing.…”

Section: Introductionmentioning

confidence: 99%

Exploiting Gangliosides for the Therapy of Ewing’s Sarcoma and H3K27M-Mutant Diffuse Midline Glioma

Wingerter

Malki

Sandhoff

et al. 2021

Cancers

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The ganglioside GD2 is an important target in childhood cancer. Nevertheless, the only therapy targeting GD2 that is approved to date is the monoclonal antibody dinutuximab, which is used in the therapy of neuroblastoma. The relevance of GD2 as a target in other tumor entities remains to be elucidated. Here, we analyzed the expression of GD2 in different pediatric tumor entities by flow cytometry and tested two approaches for targeting GD2. H3K27M-mutant diffuse midline glioma (H3K27M-mutant DMG) samples showed the highest expression of GD2 with all cells strongly positive for the antigen. Ewing’s sarcoma (ES) samples also showed high expression, but displayed intra- and intertumor heterogeneity. Osteosarcoma had low to intermediate expression with a high percentage of GD2-negative cells. Dinutuximab beta in combination with irinotecan and temozolomide was used to treat a five-year-old girl with refractory ES. Disease control lasted over 12 months until a single partially GD2-negative intracranial metastasis was detected. In order to target GD2 in H3K27M-mutant DMG, we blocked ganglioside synthesis via eliglustat, since dinutuximab cannot cross the blood–brain barrier. Eliglustat is an inhibitor of glucosylceramide synthase, and it is used for treating children with Gaucher’s disease. Eliglustat completely inhibited the proliferation of primary H3K27M-mutant DMG cells in vitro. In summary, our data provide evidence that dinutuximab might be effective in tumors with high GD2 expression. Moreover, disrupting the ganglioside metabolism in H3K27M-mutant DMG could open up a new therapeutic option for this highly fatal cancer.

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“…The shortest of the cancer associated glycolipids is GM3, which is has one sialic acid attached to the Lac-Cer structure (Birklé et al, 2003), and is highly up-regulated in brain, lung, and skin cancers (Zheng et al, 2019; Gu et al, 2008). GD2 and GD3 are longer glycans that are characterized by two sialic acids apiece and differ by an extra GalNAc structure on GD2 (Liu et al, 2018a). GD3 is a structure that is seen in low levels in healthy adults, and increases in GD3 correlate with a treatment resistant brain cancer stem cell population (Yeh et al, 2016).…”

Section: Critical Glycan Moieties Aberrantly Expressed In Cancermentioning

confidence: 99%

Don’t sugarcoat it: How glycocalyx composition influences cancer progression

Buffone

Weaver

2019

Journal of Cell Biology

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Mechanical interactions between tumors and the extracellular matrix (ECM) of the surrounding tissues have profound effects on a wide variety of cellular functions. An underappreciated mediator of tumor–ECM interactions is the glycocalyx, the sugar-decorated proteins and lipids that act as a buffer between the tumor and the ECM, which in turn mediates all cell-tissue mechanics. Importantly, tumors have an increase in the density of the glycocalyx, which in turn increases the tension of the cell membrane, alters tissue mechanics, and drives a more cancerous phenotype. In this review, we describe the basic components of the glycocalyx and the glycan moieties implicated in cancer. Next, we examine the important role the glycocalyx plays in driving tension-mediated cancer cell signaling through a self-enforcing feedback loop that expands the glycocalyx and furthers cancer progression. Finally, we discuss current tools used to edit the composition of the glycocalyx and the future challenges in leveraging these tools into a novel tractable approach to treat cancer.

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Ganglioside GD3 synthase (GD3S), a novel cancer drug target

Cited by 39 publications

References 91 publications

Sialylation of Human Natural Killer (NK) Cells Is Regulated by IL-2

Sialylation of Human Natural Killer (NK) Cells Is Regulated by IL-2

Exploiting Gangliosides for the Therapy of Ewing’s Sarcoma and H3K27M-Mutant Diffuse Midline Glioma

Don’t sugarcoat it: How glycocalyx composition influences cancer progression

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