Blocking cells’ starvation response could help beat cancer

Degradation of intracellular material in autophagy is regulated by Armus. Armus (labelled in red) co-localises with LC3 (labelled in green) in autophagosomes destined to fuse and be degraded in lysosomes.

At home, we are all used to recycle different items, by separating them into distinct containers and sending to specialised places to be destroyed into raw materials.  Cells also do the same: they destroy unwanted material into small components that can then be recycled to obtain energy and building blocks for proteins and lipids.

A recent paper published in Developmental Cell by my group (The Braga Lab) in NHLI, investigates the mechanisms of degradation of intracellular material leading to cell survival in the absence of nutrients.

This process is called autophagy and is important in a number of pathologies, including neurodegenerative diseases (where misfolded proteins are cleared out) and survival of cancer cells inside tumours.  Stopping tumour cells from doing this would improve the effectiveness of treatments and the survival of cancer patients.   However, specific inhibitors of autophagy are still being developed that could be used in clinic.

Our lab has identified a novel regulator of autophagy named Armus.  Armus facilitates the delivery of unwanted material found in specialised packages (autophagosomes) for degradation in organelles called lysosomes.   Blocking Armus function considerably delays clearing out cellular components and autophagy progression.  Armus does so by interacting directly with LC3, a protein found at autophagosomes, which then localizes Armus at the right place and time.

Inhibiting autophagy has been shown to improve the effectiveness of chemotherapy for lung and pancreatic tumours..  We found that if you stop Armus from working, the unwanted intracellular components don’t get broken down. Cells thus cannot obtain extra energy from recycling parts that helps their survival. This opens the door to developing novel drugs that targets Armus and helps conventional therapies kill cancer cells more efficiently.

Our research was funded by Cancer Research UK, the Association for International Cancer Research, the Wellcome Trust, the Brunei Government and the Biotechnology and Biological Sciences Research Council.

Dr Vania Braga
Reader in Cell-cell Adhesion Signaling, Molecular Medicine
National Heart and Lung Institute

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