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Neurotoxins and cancer cells: Gangliosides gangs up

A close-up view (click here for more details) of the proposed interface between PSGs (sialyllactose glycan shown in detail), Syts (red/blue) and BoNT/B (shown is the C-terminal domain of the heavy chain; golden). From Jin, R. et al. Botulinum neurotoxin B recognizes its protein receptor with high affinity and specificity. Nature 444, 1092-1095 (2006).

Gangliosides form membrane microdomains, which are involved in the control of cellular processes such as T cell activation. However, research on how the ganglioside's sialylated glycans contribute to specific signaling processes is still rare. Two studies now describe gangliosides as co-receptors of Clostridium botulinum neurotoxins (BoNTs) and as regulators of cancer cell migration.

The deadly potential of BoNTs is due to their proteolytic activity toward soluble NSF attachment receptor (SNARE) proteins, thus preventing synaptic vesicles to fuse with the neuronal membrane. Interestingly, mice lacking PSGs are less likely to die from BoNT exposure than wild-type mice. Structural studies have indicated low affinity interactions between polysialiogangliosides (PSGs) and type A and B BoNTs, and they have established. the synaptic vesicle proteins SV2 and synaptotagmins I/II (Syts I/II) as protein receptors for type B (BoNT/B), G (BoNT/G) and A BoNT (BoNT/A), respectively. Reporting in the Journal of Cell Biology, Dong et al. have now elucidated PSG's role in BoNT action in vivo. The authors disrupted the transferase that attaches N-acetylgalactosamine to create mice lacking PSG (GalNAc-T^-/- mice). Dong et al. found that the LD50 value (dose required to kill 50% of animals) for GalNac-T^-/- mice was 20 times higher than that for wild-type mice. Furthermore, the authors detected only residual binding of BoNT/A, B and G to hippocampal neurons from GalNAc-T^-/- mice and showed that the BoNTs did not cleave SNARE proteins in these neurons. These data also demonstrated that PSGs and Syts work together as essential functional co-receptors for BoNT/A, B and G in neurons. Interestingly, results by other groups indicate that PSGs may play a similar role in the binding of Tetanus neurotoxins.

The simplest ganglioside is GM3, which is formed by the monosialylation of lactosylceramide, and has been associated with various cancer types and stages. In Breast Cancer Research, Gu et al. observed that GM3 synthase (GM3S) levels were higher in a metastatic (4T1) than in a nonmetastatic (67NR) breast cancer cell line. Abrogation of GM3S expression by RNA interference in 4T1 cells reduced cell colonies formed in soft agar culture assays, whereas overexpression of GM3S in 67NR cells increased the colony number. Gu et al. found that inhibiting phosphatidylinositol-3-kinase (PI3K) reverted the increased protein kinase B (Akt) phosphorylation found in GM3S-silenced 4T1 cells to that found in unmodified cells, indicating that PI3K/Akt signaling is inhibited by GM3S expression. Consistent with this hypothesis, the negative PI3K/Akt regulator phosphatase and tensin homolog deleted on chromosome ten (PTEN) was found to be suppressed by GM3S inhibition. Whereas GM3S expression inhibited Akt signaling in 4T1 cells, it led to enhanced expression of the transcription factor nuclear factor of activated T cells (NFAT1). NFAT1 is known to promote cancer cell migration and invasion and is kept in check by Akt in normal cells. In sum, Gu et al. conclusively show how increased GM3 synthesis in breast cancer cells supports their enhanced migratory potential.

Taken together, both studies emphasize the need for research into the details of ganglioside involvement in cellular signaling.

Author: Mirko von Elstermann