Scientists have found that stopping translation elongation, a key step in protein production, can slow the growth of cancer cells. They identified that this works by reducing the energy producing capability of the mitochondria. We can use this finding to develop a treatment for cancers that are reliant on the mitochondria, such as acute myeloid leukaemia and mesothelioma.
Cancer is a large group of diseases where our own cells break free from their normal restrictions and grow rapidly. Whilst we often think of DNA mutations in cancer, control of protein production is also important in cancer disease development.
To make proteins, messenger RNA carries the instructions from DNA to the ribosome to assemble the protein building blocks. Once started, the ribosome moves along and reads the RNA in a step called translation elongation.
Most research has focused on the first step of translation, as this will stop all of protein production. Rebecca Raven, co-first author of this study, explains how they tried a different approach, “We used a drug called GC7 to prevent the elongation factor eIF5A1 from being turned on. This stopped the production of many proteins, but those in the mitochondria were most affected leading to mitochondria stress.”
Willis and colleagues found that this turned on the stress response pathways in the cell. This paused translation initiation and slowed growth whilst the cell tried to restore normal function. This finding suggests an alternative strategy to target cancer cells which could be used together with current cancer treatments.
The mitochondria are an important centre for energy generation in the cell. Cancer cells are energy hungry, and some types of cancer cells max out their mitochondria to meet this energy demand. The authors found that cell types that did not have any reserve mitochondria capacity were more sensitive to GC7.
GC7 isn’t used as a solo treatment for patients because its effects are too toxic. Instead, it is used to enhance the cancer cell killing ability of other drugs.
Professor Anne Willis, MRC Toxicology Unit director and senior author of this study said; “By understanding how GC7 works we can not only develop more selective drugs, but also know better when to use them. For example, colon cancer and lung adenocarcinoma have higher levels of eIF5A1, suggesting that it is important for the growth of these types of cancer.”
“Whether cells have a reserve mitochondrial capacity is not often considered when developing drugs. Understanding which normal and cancerous cell types rely on their mitochondria could help us know when to use certain treatments and avoid side effects” said Dr Rob Harvey, a researcher in the Willis group and co-author of this study.
This study was performed at Willis lab at the University of Cambridge’s MRC Toxicology Unit, collaborating with Sawarkar, MacFarlane (MRC Toxicology Unit), Turner (Babraham Institute), Sansom (CRUK Scotland Institute) and Le Quesne (University of Glasgow) labs.