TNF differentially regulates ganglioside biosynthesis and expression in breast cancer cell lines.

Justine H Dewald,Philippe Delannoy,Clément P Delannoy,Marlène Mortuaire,Agata Steenackers,Sophie Groux-Degroote,Corentin Spriet,Maxence Noël,Sumeyye Cavdarli,Aamir Ahmad

doi:10.1371/journal.pone.0196369

Abstract

Gangliosides are glycosphingolipids concentrated in glycolipid-enriched membrane microdomains. Mainly restricted to the nervous system in healthy adult, complex gangliosides such as GD3 and GD2 have been shown to be involved in aggressiveness and metastasis of neuro-ectoderm derived tumors such as melanoma and neuroblastoma. GD3 synthase (GD3S), the key enzyme that controls the biosynthesis of complex gangliosides, was shown to be over-expressed in Estrogen Receptor (ER)-negative breast cancer tumors, and associated with a decreased overall survival of patients. We previously demonstrated that GD3S expression in ER-negative breast cancer cells induced a proliferative phenotype and an increased tumor growth. In addition, our results clearly indicate that Tumor Necrosis Factor (TNF) induced GD3S over-expression in breast cancer cells via NFκB pathway. In this study, we analyzed the effect of TNF on ganglioside biosynthesis and expression in breast cancer cells from different molecular subtypes. We showed that TNF up-regulated the expression of GD3S in MCF-7 and Hs578T cells, whereas no change was observed for MDA-MB-231. We also showed that TNF induced an increased expression of complex gangliosides at the cell surface of a small proportion of MCF-7 cells. These results demonstrate that TNF differentially regulates gangliosides expression in breast cancer cell lines and establish a possible link between inflammation at the tumor site environment, expression of complex gangliosides and tumor development.

Highlights

Gangliosides define as subclass of acidic glycosphingolipids (GSL) carrying one or more sialic acid residues in the carbohydrate moiety
Changes in the structure of gangliosides can occur under pathological conditions [7,8,9] and a neo-expression of disialogangliosides such as GD2 and GD3 is observed in several cancers from neuroectoderm origin including melanoma and neuroblastoma, in which they play a key role in invasion and metastasis [10], and disialogangliosides are attractive targets for cancer immunotherapy [11,12]
The composition of total GSL was determined by MALDI-TOF mass spectrometry after permethylation in three commonly used breast cancer cell lines, i.e. the luminal-A MCF-7 cells, the basal-like MDA-MB-231 cells, whose ganglioside composition was already analyzed [16], and the basal-like Hs578T cells, whose ganglioside profile appeared to be quite different from the two other cell lines (Fig 2 and Table 2)

Summary

Introduction

Gangliosides define as subclass of acidic glycosphingolipids (GSL) carrying one or more sialic acid residues in the carbohydrate moiety. The carbohydrate moiety of gangliosides is synthesized in the Golgi apparatus by specific glycosyltransferases (GT) and gangliosides are classified in four series according to the number of sialic acid residues linked to the lactosylceramide (Fig 1). Changes in the structure of gangliosides can occur under pathological conditions [7,8,9] and a neo-expression of disialogangliosides such as GD2 and GD3 is observed in several cancers from neuroectoderm origin including melanoma and neuroblastoma, in which they play a key role in invasion and metastasis [10], and disialogangliosides are attractive targets for cancer immunotherapy [11,12]

Methods

Results

Conclusion