ISSN: 1449-2288International Journal of Biological Sciences
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Int J Biol Sci 2017; 13(3):265-275. doi:10.7150/ijbs.16903 This issue Cite
Research Paper
Disialyl GD2 ganglioside suppresses ICAM-1-mediated invasiveness in human breast cancer MDA-MB231 cells
1. Molecular and Cellular Glycobiology Unit, Department of Biological Sciences, Sungkyunkwan University, Seoburo 2066, Jangan-Gu, Suwon, Gyunggi-Do, 16419, Korea;
2. Research Institute, Davinch-K Co., Ltd., B1603-3, 606, Seobusaet-gil, Geumcheon-gu, Seoul 153-719, Korea;
3. Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan City, Gyeongsangnam-Do, Korea;
4. Animal Biotechnology Division, National Institute of Animal Science, RDA, Wanju-gun, Jeollabuk-do, 55365, Korea;
5. Division of Enteric Diseases, Center for Infectious Diseases Research, Korea National Institute of Health, Heungdeok-gu, Cheongju 363-951, Korea;
6. Department of Biotechnology, Dong-A University, Busan 604-714, Korea;
7. Department of Herb Science, Dong-Eui Institute of Technology, 54, Yangji-ro, Busanjin-Gu, Busan 47230, Korea;
8. Department of Medical Device Management and Research, Samsung Advanced Institute of Health Science and Technology (SAIHST), Seoul 06351, Korea.
Abstract
The disialoganglioside GD3 has been considered to be involved in tumor progression or suppression in various tumor cells. However, the significance of the biological functions of GD3 in breast cancer cells is still controversial. This prompted us to study the possible relationship(s) between GD3 expression and the metastatic potential of a breast cancer MDA-MB231 cells as an estrogen receptor negative (ER-) type. The human GD3 synthase cDNA was transfected into MDA-MB231 cells, and G-418 bulk selection was used to select cells stably overexpressing the GD3 synthase. In vitro invasion potentials of the GD3 synthase over-expressing cells (pc3-GD3s) were significantly suppressed when compared with control cells. Expression of intercellular adhesion molecule-1 (ICAM-1; CD54) was down-regulated in the pc3-GD3s cells and the decrease in ICAM-I expression is directly related to the decrease in invasiveness of the pc3-GD3s cells. Another type of ER negative SK-BR3 cells exhibited the similar level of ICAM-1 expression as MDA-MB231 cells, while the ER positive MCF-7 cells (ER+) showed the increased expression level of ICAM-1. Then, we investigated signaling pathways known to control ICAM-1 expression. No difference was observed in the phosphorylation of ERK and p38 between the pc3-GD3s and control cells (pc3), but the activation of AKT was inhibited in pc3-GD3s, and not in the control (pc3). In addition, the composition of total gangliosides was changed between control (pc3) and pc3-GD3s cells, as confirmed by HPTLC. The pc3-GD3s cells had an accumulation of the GD2 instead of the GD3. RT-PCR results showed that not only GD3 synthase, but also GM2/GD2 synthase (β4-GalNc T) expression was increased in pc3-GD3s cells. Overexpression of GD3 synthase suppresses the invasive potential of human breast cancer MDA-MB-231 cells through down-regulation of ICAM-1 and the crucial pathway to allow the apoptotic effect has been attributed to accumulation of the GD2 ganglioside. ER has been linked to the ICAM-1 expression with GD3 to GD2 conversion in human breast cancer cells. This is the first finding of the endogenous sialyltransferase functions in tumor cells.
Keywords: Ganglioside GD3 synthase, Breast cancer, MDA-MB231, Intracellular adhesion molecule-1, GM2/GD2 synthase (β4-GalNc T), Invasion.
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