Polysialic acid sustains cancer cell survival and migratory capacity in a hypoxic environment

Abstract

Polysialic acid (polySia) is a unique carbohydrate polymer expressed on the surface of NCAM (neuronal cell adhesion molecule) in a number of cancers where it modulates cell-cell and cell-matrix adhesion, migration, invasion and metastasis and is strongly associated with poor clinical prognosis. We have carried out the first investigation into the effect of polySia expression on the behaviour of cancer cells in hypoxia, a key source of chemoresistance in tumours. The role of polysialylation and associated tumour cell migration and cell adhesion were studied in hypoxia, along with effects on cell survival and the potential role of HIF-1. Our findings provide the first evidence that polySia expression sustains migratory capacity and is associated with tumour cell survival in hypoxia. Initial mechanistic studies indicate a potential role for HIF-1 in sustaining polySia-mediated migratory capacity, but not cell survival. These data add to the growing body of evidence pointing to a crucial role for the polysialyltransferases (polySTs) in neuroendocrine tumour progression and provide the first evidence to suggest that polySia is associated with an aggressive phenotype in tumour hypoxia. These results have significant potential implications for polyST inhibition as an anti-metastatic therapeutic strategy and for targeting hypoxic cancer cells.

Cooperation of HIF‐ and NCAM‐mediated mechanisms in cell viability of hippocampal cultures after oxygen–glucose deprivation

“…NCAM assemble with NCAMs of adjacent cells via homophilic interactions or associates with other protein via heterophilic interactions (Cavallaro et al, 2001;Berezin, 2010;Cavallaro and Dejana, 2011). The disruption of NCAM function affects signaling pathways and has detrimental consequences for cell viability (Shichi et al, 2011;Elkashef et al, 2016). The disruption of NCAM function affects signaling pathways and has detrimental consequences for cell viability (Shichi et al, 2011;Elkashef et al, 2016).…”

“…It is known that FGFR is one of NCAM binding partners in modulation of signal transduction (Francavilla et al, 2007). The disruption of NCAM function affects signaling pathways and has detrimental consequences for cell viability (Shichi et al, 2011;Elkashef et al, 2016).…”

“…NCAM determines cell adhesion, migration, proliferation, and survival (Berezin, 2010;Elkashef et al, 2016). NCAM determines cell adhesion, migration, proliferation, and survival (Berezin, 2010;Elkashef et al, 2016).…”

“…Among many factors that mediate structural and functional integrity of neuronal tissue, neural cell adhesion molecules (NCAMs) occupy a key position. NCAM determines cell adhesion, migration, proliferation, and survival (Berezin, 2010;Elkashef et al, 2016). The adhesive and signaling functions of NCAM are executed via homophilic interactions with NCAMs of adjacent cells or heterophilic interactions with other molecules, including well-known multifunctional mediator of cellular processes-FGFR (fibroblast growth factor receptor) (Francavilla et al, 2007;Cavallaro and Dejana, 2011).…”

Glycation Leads to Increased Polysialylation and Promotes the Metastatic Potential of Neuroblastoma Cells

“…Since cell surface sialylation and polysialylation are prognostic markers of several tumors [21], we then quantified membrane bound sialic acids and polysialic acids of Kelly cells cultured in the absence or presence of 100 µM MGO. We found that MGO treatment increased the total sialic acids on cell surface proteins by nearly 50% ( Figure 3A).…”