Institute of Life Sciences researchers have discovered that downregulation of a protein drug target can help in the treatment of cancers, while activation can do the same for neurodegerative diseases such as Alzheimer’s, Parkinson’s and amyotrophic lateral sclerosis. They have identified the novel mechanism by which misfolded proteins form aggregates and get degraded in the cells.
Bhubaneswar-based researchers have discovered that activation of a particular protein (TRIM16) can turn out to be a potential therapeutic intervention strategy for neurodegenerative diseases such as Alzheimer’s, Parkinson’s and amyotrophic lateral sclerosis (ALS). At the same time, inhibiting this protein in cancer cells can bring about a reduction in tumour proliferation. The results were published in The EMBO Journal.
Studies carried out in test tubes and in mice models have shown that the protein has the ability to protect cancer cells from oxidative stress, and inhibiting this protein can therefore lead to reduced tumour growth.
Normally, about 30% of newly synthesised proteins in a cell can end up being misfolded, which are then degraded and removed from the cell. Genetic mutations and stress (both cellular and environmental) can increase the rate of misfolding. When the amount of misfolded proteins far exceeds the capacity of cells to degrade and clear them, the cells tend to aggregate the misfolded proteins to reduce toxicity.
Though protein aggregates are less toxic to cells, they too can turn toxic if the aggregates increase in number and size, which is what is seen in the case of Alzheimer’s, Parkinson’s and ALS.
A team of researchers led by Dr. Santosh Chauhan from the Cell Biology and Infectious Diseases Unit at the Institute of Life Sciences, Bhubaneswar has identified the novel mechanism by which misfolded proteins form aggregates and get degraded in the cell.
Role of TRIM16 protein
They found the TRIM16 protein playing a role both in the formation of protein aggregates and in their degradation. Protein aggregates are formed when the TRIM16 protein activates a particular pathway (P62-NRF2), while protein aggregates get degraded when TRIM16 enhances a different pathway (autophagy). Autophagy is a process of degrading the unwanted material to clean the cells and keep them healthy.
“The current strategy is to use small molecules to enhance the autophagy process to destroy protein aggregates. But small molecules are non-specific and can target other pathways too,” says Dr. Chauhan, who is an Intermediate Fellow of the Wellcome Trust-DBT India Alliance. “Pharmacological activation of TRIM16 protein, on the other hand, will be more specific for therapeutic targeting of neurodegenerative diseases.” When more TRIM16 protein is produced by activation, autophagy gets enhanced leading to higher rate of protein aggregate degradation.
Reducing cancer proliferation
Since cancer cells proliferate rapidly unlike normal cells, plenty of metabolic waste gets generated and accumulated inside cancer cells. In this study, the researchers have shown that cancer cells via TRIM16 can hijack both the autophagy and P62-NRF2 pathways to keep the cells clean and survive in harsh conditions. The P62-NRF2 pathway detoxifies the reactive oxygen species-related metabolic waste.
When the TRIM16 activity was reduced in cancer cells in vitro, the capacity to proliferate was reduced. “The cancer cells were able to grow normally when the researchers added (complemented) TRIM16 protein, thus validating the crucial role of TRIM16 in cancer cell growth,” says Kautilya Kumar Jena from the Institute’s Cell Biology and Infectious Diseases Unit and first author of the paper.
In the case of animal studies, the researchers first removed (knockout) the TRIM16 protein from cancer cells and then introduced the cancer cells into mice models. “Compared with controls, tumour growth was drastically reduced in mice when cancer cells did not have the TRIM16 protein,” says Chauhan. “If we pharmacologically decrease the activity of TRIM16 in cancer cells then tumour growth can be inhibited.”