Researchers zero in on a special type of RNA to combat cancer

A certain type of RNA (ribonucleic acid, which is present in our body cells and regulates how genes produce various proteins) is being looked at closely for a cancer cure.

Among the several types of RNAs, the micro-RNA, or miRNA, influences how genes make proteins. In other words, miRNA can kill a cell or help it proliferate. (miRNA is different from mRNA, or messenger RNA, which has been in the news recently as a coronavirus vaccine.)

“Altering miRNA levels in cancer cells has promising potential as a therapeutic intervention,” says a 2020 paper published in the National Library of Medicine of the US government.

So, the miRNA has created a buzz among medical biotechnologists for its cancer fighting role. It works for sure, but there are hurdles, such as stability and how to deliver it into the body.

There is ongoing research to find out which miRNA works best for which type of cancer, how to make it and how to deliver it into the body. This approach to cancer therapy gains even more importance when compared with conventional cancer therapies such as chemo, radiation and surgery, which end up killing the good cells of the body, too.

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Now, researchers from two institutions in Chennai have reported a breakthrough. Prof Karunagaran Devarajan of the department of biotechnology, IIT-Madras, and Dr Sandhya Sundaram, pathologist, and Dr Ganesh Venkatraman of the department of human genetics, faculty of biomedical sciences, at Sri Ramachandra Medical College and Research Institute, have reported successfully using a particular miRNA for treating breast cancer.

How it works

As in any cell, the cell wall (membrane) of the cancerous cell is made up of lipids (fatty acids) and proteins.

The lipids are prone to get oxidised (like iron rusting), which is bad; but there is a defence mechanism — anti-oxidants — in the cell that prevents lipids from oxidising.

But if iron accumulates within the cell, the anti-oxidants are busy neutralising the iron, leaving the lipids of the cell walls defenceless.

A protein called SLC7A11 prevents iron from accumulating in the cell. Like other proteins, it is produced by genes.

RNAs in the cell regulate gene expression — the process by which genes make copies of proteins. The micro-RNA miR-5096 “down-regulates” or lowers the production of the SLC7A11 protein.

With not enough SLC7A11, iron accumulates within the cell, which exhausts the defending capacity of the anti-oxidants, leaving the lipids in the cell walls open to external oxidisation (lipid peroxidisation). The lipids “rust away”, the cell wall collapses, and the cancer cell dies. This method of killing a cell is called ferroptosis.

In this cancer, especially among Indian women, a protein called SLC7A11 gets over-produced in the cancer cells. The traditional way of treating this is to use drugs such as sulfasalazine to inhibit the production of this protein. In the latest development, the researchers have identified an miRNA, called miR-5096, as the one that is effective against breast cancer.

miR-5096 was found to induce cell death by suppressing the SLC7A11 protein. “This is the first time miR-5096 has been studied and used to target SLC7A11 in breast cancer cells. The cell death occurs by a process known as ferroptosis,” says an article on the IIT-M website.

Ferroptosis is a way of killing cells (programmed cell death) that was discovered a decade ago, where cells die when iron accumulates inside them. Now, iron means rust, and the anti-oxidants in the body fight this rust. This way, the accumulated iron uses up all the anti-oxidants in the cell, leaving the cell membrane defenceless against the oxidation that happens naturally. Cell membranes are made up of lipids and proteins. The lipids get oxidised (called lipid peroxidation) and the cell membrane collapses, killing the cell.

The researchers demonstrated that miR-5096 targets and inhibits the production of the protein SLC7A11. This protein protects the cell from ferroptosis. When the miR-5096 inhibits the production of the protein, it leads to a pile-up of iron in the cells, ferroptosis, and, eventually, cell death. “The results of the study prove that miR-5096 can effectively kill breast cancer cells,” says IIT-M, adding that they highlight the therapeutic potential of ferroptosis in breast cancer.

Dr Sundaram told Quantum that breast cancer was chosen to test the efficacy of miR-5096 because “this is the commonest form of cancer that I diagnose in my routine practice... the effectiveness in other cancer models has not been tested but further research may yield interesting results”.

She said that to target SLC7A11, which protects breast cancer cells from ferroptotic cell death, “we used bio-informatic target prediction tools like TargetScan, miR-WALK, and got an indication that miR-5096 might target the protein SLC7A11”. The micro-RNA is present in human cells and can be replicated in a lab, she said.

Currently, micro-RNAs have gone into pre-clinical trials; scientists are working with cancer in animals, but that disease is not an exact replica of the human disease, Dr Sundaram said. Further, cancer cells also use several pathological mechanisms to sustain, proliferate and evade treatments, she observed. However, the miR-5096 is a breakthrough; with validation in clinical trials, it can turn out to be an effective cancer cure.

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