CANCER drugs which inhibit the activities of E3 ubiquitin ligases could be repurposed to treat vascular inflammation, according to researchers from the University of California, San Diego, California, USA.
Ubiquitination of GPCRs
This was stated following an analysis of the functions and structure of G-protein-coupled receptors (GPCRs) in endothelial cells by the team; this is important because malfunctions in GPCRs, which act as signal transducers and are embedded in cell membranes, can lead to the development of numerous diseases due to their vital role in most biological functions, such as heart rate, blood pressure, and vision, smell, taste, and allergic responses.
“We were surprised to discover that GPCRs and inflammation are influenced by ubiquitination, a process that was previously thought to only mark proteins for destruction,” said senior author Prof JoAnn Trejo, University of California, San Diego. “Instead, we’ve unveiled new insights into both GPCR function and ubiquitination.”
In the study, the team observed that ubiquitination of GPCRs triggers a series of events that promote inflammation. They found that when GPCRs are tagged with ubiquitin, they turn on the enzyme E3 ligase which actually conducted this tagging. This then sparks a number of molecular events leading to another protein called p38 being activated, which in turn promotes inflammation.
The function of ubiquitination of GPCRs differs from that normally seen with other cells; usually a ubiquitin tag makes the cell’s disposal machinery aware that a protein is ready for degradation.
Repurposing Cancer Drugs
These findings open up the possibility of FDA-approved cancer drugs that inhibit E3 ubiquitin ligases being utilised to treat vascular inflammation as well. There are other such drugs that have entered clinical trials and could also potentially be used in this way in the future.
“But given the large number of E3 ligases in the human body – there are between 600 and 700 – and their diverse functions, the number of E3-targeting drugs approved or in clinical trials is remarkably small,” commented Prof Trejo. “And this is the first time E3 ligases have been shown to also play a role in vascular inflammation, which broadens the potential applications for drugs that inhibit these enzymes. The field is really in its infancy.”