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The biological role and immunotherapy of gangliosides and GD3 synthase in cancers.

ABSTRACT: Gangliosides are a large subfamily of glycosphingolipids that broadly exist in the nervous system and interact with signaling molecules in the lipid rafts. GD3 and GD2 are two types of disialogangliosides (GDs) that include two sialic acid residues. The expression of GD3 and GD2 in various cancers is mostly upregulated and is involved in tumor proliferation, invasion, metastasis, and immune responses. GD3 synthase (GD3S, ST8SiaI), a subclass of sialyltransferases, regulates the biosynthesis of GD3 and GD2. GD3S is also upregulated in most tumors and plays an important role in the development and progression of tumors. Many clinical trials targeting GD2 are ongoing and various immunotherapy studies targeting gangliosides and GD3S are gradually attracting much interest and attention. This review summarizes the function, molecular mechanisms, and ongoing clinical applications of GD3, GD2, and GD3S in abundant types of tumors, which aims to provide novel targets for future cancer therapy.

SUBMITTER: Cao S

PROVIDER: S-EPMC9941352 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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The biological role and immunotherapy of gangliosides and GD3 synthase in cancers.

Cao Shangqi S Hu Xu X Ren Shangqing S Wang Yaohui Y Shao Yanxiang Y Wu Kan K Yang Zhen Z Yang Weixiao W He Gu G Li Xiang X

Frontiers in cell and developmental biology 20230207

Gangliosides are a large subfamily of glycosphingolipids that broadly exist in the nervous system and interact with signaling molecules in the lipid rafts. GD3 and GD2 are two types of disialogangliosides (GDs) that include two sialic acid residues. The expression of GD3 and GD2 in various cancers is mostly upregulated and is involved in tumor proliferation, invasion, metastasis, and immune responses. GD3 synthase (GD3S, ST8SiaI), a subclass of sialyltransferases, regulates the biosynthesis of G ...[more]

PMID: 36824365

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Project description:The epithelial-mesenchymal transition (EMT) bestows cancer cells with increased stem cell properties and metastatic potential. To date, multiple extracellular stimuli and transcription factors have been shown to regulate EMT. Many of them are not druggable and therefore it is necessary to identify targets, which can be inhibited using small molecules to prevent metastasis. Recently, we identified the ganglioside GD2 as a novel breast cancer stem cell marker. Moreover, we found that GD3 synthase (GD3S)--an enzyme involved in GD2 biosynthesis--is critical for GD2 production and could serve as a potential druggable target for inhibiting tumor initiation and metastasis. Indeed, there is a small molecule known as triptolide that has been shown to inhibit GD3S function. Accordingly, in this manuscript, we demonstrate that the inhibition of GD3S using small hairpin RNA or triptolide compromises the initiation and maintenance of EMT instigated by various signaling pathways, including Snail, Twist and transforming growth factor-β1 as well as the mesenchymal characteristics of claudin-low breast cancer cell lines (SUM159 and MDA-MB-231). Moreover, GD3S is necessary for wound healing, migration, invasion and stem cell properties in vitro. Most importantly, inhibition of GD3S in vivo prevents metastasis in experimental as well as in spontaneous syngeneic wild-type mouse models. We also demonstrate that the transcription factor FOXC2, a central downstream effector of several EMT pathways, directly regulates GD3S expression by binding to its promoter. In clinical specimens, the expression of GD3S correlates with poor prognosis in triple-negative human breast tumors. Moreover, GD3S expression correlates with activation of the c-Met signaling pathway leading to increased stem cell properties and metastatic competence. Collectively, these findings suggest that the GD3S-c-Met axis could serve as an effective target for the treatment of metastatic breast cancers.

Dataset Information

The biological role and immunotherapy of gangliosides and GD3 synthase in cancers.

Publications

The biological role and immunotherapy of gangliosides and GD3 synthase in cancers.

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