Novel mechanisms regulating Notch signaling: the importance of intracellular vesicles : “When Notch, a metal transporter, and an antimalarial drug meet…”

Notch is a protein that is often highly active in tumours. To activate Notch it must be cleaved and transported to the cell nucleus, where it activates tumour cell growth. The aim of this promotion research was to study the differences between Notch activation in tumours and healthy tissues. This new knowledge may lead to the development of novel cancer treatments that more specifically attack tumour cells, without affecting healthy tissues. This will result in more effective treatments with less adverse effects.
This promotion research shows that transport vesicles are essential for Notch activation in the cell. Combining Notch inhibitors with transport inhibitor chloroquine inhibits Notch resulting in an inhibition of cell growth and activation of cell death in leukemic cells. Moreover, the research shows that the Dmt1 protein, which transports iron in the cell, can both activate and inhibit Notch activity. Many tumours are addicted to iron since iron stimulates cell growth and promotes metastasis. Making smart use of this new knowledge may lead to the development of Dmt1 inhibitors that can inhibit both Notch activation and iron uptake in tumours.
In conclusion, the findings described in my thesis show that Notch activation is very complex and depends on transport vesicles in the cell. Manipulation of this transport may inhibit Notch specifically in tumours without affecting normal tissues. Lastly, my findings show that cleaved Notch is not always active if it is not located to the cell nucleus.