For a cell to grow and divide, it needs to produce new proteins. This also applies to cancer cells. In a new study published today in Science Advances, researchers at Karolinska Institutet in Sweden have investigated the protein eukaryotic initiation factor 4A-III (eIF4A3) and its role in the growth of cancer cells. The study shows that by blocking or reducing the production of this protein, other processes arise that cause the growth and cell division of cancer cells to cease and eventually die.
EIF4A3 is essential for mRNA splicing, transport, translation, and surveillance. Recently, investigations have focused on EIF4A3 dysfunction in carcinogenesis. In the study, the researchers investigated cultured cancer cells and cancer tissue where the eIF4A3 protein’s expression was high compared to normal tissue. By adding synthetically produced small molecules that can later be further developed into finished drugs, the production of eIF4A3 can be checked.
They learned that the protein’s tumor-promoting functions are involved in two processes in cancer cells: ribosome biogenesis (RiBi) and p53 regulation. RiBi refers to a multistep process involving a range of factors to perform and coordinate ribosomal DNA (rDNA) transcription, ribosomal RNA (rRNA) processing, and assembly with ribosomal proteins complexes that eventually form the ribosome.
“Firstly, we saw that the blocking of eIF4A3 activated the protein p53, a protein that has an important role to play in fighting cancer cells,” says Dimitris Kanellis, a postdoctoral fellow at the Department of Medical Biochemistry and Biophysics, and the first author of the study.
However, one challenge with many types of tumors is that the positive functions of the p53 protein are counteracted by another protein, MDM2.
“Interestingly, we noted that the blocking eIF4A3 also meant that the MDM2 protein changed. This change helps to maintain and strengthen p53 and can be beneficial when we want to inhibit the growth of cancer cells,” adds Kanellis.
The main conclusions of the study indicate that depletion or inhibition of eIF4A3 activates p53, alters the manufacturing process of proteins by disrupting ribosome biogenesis, and thereby inhibits the growth of cancer cells.
“This renders eIF4A3 an exploitable vulnerability in high-RiBi tumors,” the authors write in their paper, opening up previously unidentified avenues for cancer treatment by targeting the eIF4A3 protein. “Notably, the robustly up-regulated RiBi rates in certain cancers, coupled to the dependence of cancer cells on eIF4A3 for growth and survival, highlight a previously unknown mechanistic understanding of an emerging cancer vulnerability with the potential to inspire future therapeutic strategies in oncology.”
“The discovery is very relevant, for example in colon cancer where cancer cells often have a high level of ribosomes and rapid growth. Another example is a sarcoma, cancer of the body’s support tissues, where we know that sometimes there is an overproduction of MDM2. This increases the chances of more effective treatment,” says Associate Professor Mikael Lindström and Professor Jiri Bartek, corresponding authors in the study.
“There may also be synergies between the chemical compounds that block eIF4A3 and drugs that are already used to treat cancer that we will now research further,” says co-author Associate Professor Mikael Lindström.
