Antibiotics to block cancer metastasis?

Metastasis is the spread of cancer from the primary tumor to other vital organs and is the cause of 90% of deaths related to this disease. For this expansion to take place, cancer cells have to survive unfavorable conditions, such as a lack of oxygen or a shortage of nutrients, and to overcome these stressors, they also need to adapt their energy production.

Dr. Salvador Aznar Benitah and Dr. Gloria Pascual, both from the Barcelona Biomedical Research Institute (IRB Barcelona), have participated in a study led by Dr. Michaela Frye from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) which has revealed that the NSUN3 protein is essential for the metabolic plasticity required by metastatic cells.

NSUN3 is a mitochondrial protein that regulates the production of new proteins, necessary to start the electron transport chain and thus ensure efficient energy consumption in the cell. Blocking the production of mitochondrial proteins, either by directly inhibiting NSUN3 or through the use of antibiotics such as doxycycline or chloramphenicol, reduces the formation of metastases very significantly.

“Metastasis is a process that consumes a lot of energy and, therefore, the cells that initiate it need to be very efficient in fat metabolism,” explains Dr. Aznar Benitah, ICREA researcher and head of the Stem Cells and Cancer Laboratory from IRB Barcelona. “Although additional studies are needed, this discovery is very encouraging, because it opens a new avenue for the possible treatment of metastases,” he adds.

Salvador Aznar Benitah leads the Stem Cells and Cancer Laboratory at IRB Barcelona. (Photo: IRB Barcelona)

“The importance of mitochondrial RNA modifications has been previously studied in certain metabolic diseases, but now we show, for the first time, that there is a direct relationship between mitochondrial tRNA modifications and cancer metastasis,” says Dr. Frye.

Mitochondria are small membrane-bound organelles that act as a “powerhouse” for the cells in our body. To produce energy, they use the so-called “respiratory chain”, which is located in the mitochondrial membrane. Since they contain their own genetic material, it is the mitochondria themselves that produce the essential components of the respiratory chain.

The production of respiratory chain components is tightly regulated by specific machinery in the mitochondria, and NSUN3 plays a crucial role in this process. The new study reveals how the production of mitochondrial proteins is essential for the metastatic process.

Because of the similarity of bacterial membranes to those of mitochondria, certain antibiotics slow down mitochondrial protein synthesis without affecting “general” protein synthesis in the cell. Therefore, the researchers hypothesized that these agents should affect cancer cells in a similar way to the loss of NSUN3.

Following this approach, the research team later found that treatment with antibiotics such as chloramphenicol or doxycycline did reduce the invasive spread of cancer cells. Antibiotic administration also reduced the number of metastases in mouse model lymph nodes.

The team led by Dr. Frye discovered that a specific chemical modification found in mitochondrial tRNA, known as “m5C” (5-methylcytosine), is necessary for the development of metastasis. Modification of m5C increases protein synthesis in the mitochondria, thereby increasing the production of respiratory chain components. As a result, the cell increases its energy reserve to fuel cellular processes that consume a large amount of energy, such as the spread of cancer cells from a tumor.

Instead, cancer cells that lack m5C obtain their energy through a comparatively less efficient mechanism called “glycolysis,” and have a limited capacity for metastatic spread. The researchers demonstrated this using human tumors grown in mice. However, neither the viability nor the growth of cells in the primary tumor was affected by the absence of m5C.

A specific enzyme, NSUN3 methyltransferase, is responsible for the modification of m5C RNA. When the scientists deactivated NSUN3, the mitochondrial tRNA was changed to a lesser extent and the invasive spread of cancer cells decreased.

Could NSUN3 function as a biomarker for metastatic cancer? Gene expression signatures indicating elevated levels of cellular NSUN3 and elevated levels of m5C were indeed predictive of lymph node metastases and more severe disease progression in head and neck cancer patients.

Inhibition of NSUN3 is a promising way to slow down metastasis because the enzyme is solely responsible for the m5C RNA tag that promotes metastasis. However, further exploration of possible long-term side effects of blockade of mitochondrial protein synthesis is necessary first.

The study is titled “Mitochondrial RNA modifications shape metabolic plasticity in metastasis.” And it has been published in the academic journal Nature. (Source: DKFZ / IRB Barcelona)