Modifications in mitochondrial RNA can make it more likely that cancer will spread and become metastatic, according to researchers at the German Cancer Research Center in Heidelberg.
Metastasis is the main cause of cancer deaths, but why it happens when it does and how to stop the spread is poorly understood. In this study, the scientists found that a specific gene signature linked with increased levels of these RNA modifications in the mitochondria predicted poor prognosis and metastasis in patients with head and neck cancer.
Notably, when the researchers blocked the action of an enzyme responsible for the RNA changes in cancer cell lines in the lab, they found metastases were reduced. They also experimented with antibiotics such as chloramphenicol or doxycycline on the cancer cells, which are known to block the production of mitochondrial proteins but not other proteins, and found that invasive spread was blocked.
“The importance of mitochondrial RNA modifications was previously studied in certain metabolic diseases. But we now show for the first time that there is a direct link between mitochondrial tRNA modifications and invasive spread of cancer,” commented lead researcher Michaela Frye, a professor at the German Cancer Research Center, in a press statement.
Mitochondria are the energy providers of the cells. Small and bacteria-like in structure, they have their own circular genomes and RNA. This includes transfer (t)RNA, small RNA molecules that help the genetic code in the messenger (m)RNA become a usable protein.
Writing in Nature, Frye and colleagues show how 5-methylcytosine modifications in mitochondrial tRNA can result in excessive mitochondrial mRNA production, which in turn powers cancer metastasis by providing energy. Cancer cells can survive using a different energy source from a process called glycolysis, but it is less efficient and makes it difficult for them to spread.
The researchers found the methyltransferase enzyme NSUN3, is responsible for the tRNA modifications. When this enzyme was deactivated in a cancer cell line, the metastatic spread was much reduced.
When a group of patients with head and neck cancer were tested for presence of high cellular NSUN3 levels, these plus high 5-methylcytosine, were linked with lymph node metastases and more severe disease progression.
The team also used a mouse model to show that antibiotics with the ability to block mitochondrial protein synthesis, such as chloramphenicol or doxycycline, could help block cancer spread and lymph node metastases in the same way as blocking the action of the NSUN3 protein.
“Inhibition of NSUN3 is a promising way to slow down metastasis because the enzyme is solely responsible for metastasis-promoting 5-methylcytosine RNA label. However, the potential long-term side effects of blocking mitochondrial protein synthesis must first be further explored,” concluded Frye.
