Study shows how mitochondrial RNA changes enhance invasive growth of cancer cells

The energy centers of cells and mitochondria have their own genetic material and RNA molecules. Researchers from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) have recently shown that certain alterations in mitochondrial RNA facilitate protein production in mitochondria, which promotes the invasive expansion of cancer cells.

Study shows how mitochondrial RNA changes enhance invasive growth of cancer cells
Mitochondria are tiny, membrane-enveloped structures known as the powerhouse of every cell in our body. Modifications of mitochondrial RNA cranks up protein synthesis and drives metastasis. Image Credit: Adobe Stock.

Researchers have proven that poor prognosis and metastasis are linked to a particular gene expression pattern that correlates with high levels of mitochondrial RNA alterations in patients with head and neck cancer.

The amount of metastases decreased when the researchers inhibited the RNA-modifying enzyme that was responsible for cancer cells. In lab tests, certain antibiotics that block protein synthesis in mitochondria also worked to stop the invasive invasion of cancer cells. The results thus far have been published in the journal Nature.

Aggressive tumors’ cancerous cells infiltrate the tissue around them in an effort to start new tumors in other organs. Cancer cells must survive difficult circumstances including a lack of oxygen or nutrition throughout their travel. Cancer cells modify their energy output to counteract these stresses. Up until now, the molecular processes causing this flexibility were not well understood.

However, we suspected that this metabolic plasticity must be a key to the successful spread of the cancer cells.”

 Michaela Frye, Cell Biologist, German Cancer Research Center

Every cell in the human body has mitochondria, which are microscopic, membrane-enclosed organelles known as the organism’s power plant. They utilize the so-called respiratory chain found in the mitochondrial membrane to produce energy. Since mitochondria have their own genetic material, they can create essential respiratory chain elements on their own.

As Michaela Frye and her colleagues have recently found and reported in the journal Nature, the synthesis of components of the respiratory chain is strictly regulated by particular machinery in the mitochondria. This finding has ramifications for the metastatic spread of cancer cells.

The tRNA molecules that make up this apparatus are in charge of supplying the various amino acid building blocks necessary for protein synthesis. The study team determined the control mechanism to enhance the production of proteins during metastasis, be the deposition of molecular changes on mitochondrial tRNAs.

RNA modifications regulate mitochondrial function and drive metastasis

Invasion of cancer cells requires a lot of energy. The researchers in Heidelberg showed that the formation of metastases depends on a particular chemical alteration called “m5C” (5-methylcytosine), which is present in mitochondrial tRNA. In the mitochondria, the m5C mutation speeds up protein synthesis.

As a result, the generation of respiratory chain components is improved. As a result, the cell’s supply of energy grows to support demanding cellular functions like the spread of cancer cells from the tumor.

On the other hand, cancer cells deficient in m5C get their energy via a rather inefficient process termed glycolysis and have a constrained capacity for metastatic expansion. The researchers used mouse-grown human tumors to show this. However, the original tumor’s cell viability or development was unaffected by the loss of m5C.

RNA-modifying enzyme as a biomarker for metastatic tumors

The alteration of the m5C RNA is carried out by a particular enzyme called the methyltransferase NSUN3. The amount of mitochondrial tRNA modification and the propagation of the cancer cells was reduced when the researchers turned down NSUN3.

Could NSUN3 serve as a biomarker for cancer have metastasized? In fact, in patients with head and neck cancer, gene expression profiles showing higher m5C and high cellular NSUN3 levels were predictive of lymph node metastases and more aggressive disease progression.

Antibiotics repurposed to block mitochondrial protein synthesis slow down metastasis

Some antibiotics reduce plasma protein synthesis in the cell without impacting “general” protein synthesis in the mitochondria. Therefore, the researchers reasoned that these substances ought to have an effect on cancer cells that is comparable to NSUN3 loss. In fact, therapy with antibiotics like doxycycline or chloramphenicol curbed the invasive growth of cancer cells. In a mouse model, the number of lymph node metastases was similarly decreased by antibiotic therapy.

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.”

Michaela Frye, Cell Biologist, German Cancer Research Center

The researcher is satisfied that new strategies to perhaps stop the spread of advanced tumors have been discovered as a result of the work done by their group.

Inhibition of NSUN3 is a promising way to slow down metastasis because the enzyme is solely responsible for metastasis-promoting m5C RNA label. However, the potential long-term side effects of blocking mitochondrial protein synthesis must first be further explored.”

Michaela Frye, Cell Biologist, German Cancer Research Center

Source:
Journal reference:

Delaunay, S., et al. (2022) Mitochondrial RNA modifications shape metabolic plasticity in metastasis. Nature. doi.org/10.1038/s41586-022-04898-5.

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