Small RNA Molecules Are Ancient Kill Switches that Cause Cancer Cell Death, Study Reveals

Small RNA Molecules Are Ancient Kill Switches that Cause Cancer Cell Death, Study Reveals

A recent study reports that small RNA molecules, siRNAs and shRNAs, may contain sequences that simultaneously target multiple survival genes, which ultimately causes efficient cancer cell death. This discovery, eight years in the making, could eventually have an impact on multiple cancers.

The study, “Many si/shRNAs can kill cancer cells by targeting multiple survival genes through an off-target mechanism,” was published in eLife. 

“Our research may be tapping into one of nature’s original kill switches, and we hope the impact will affect many cancers,” lead researcher Marcus Peter, professor of cancer metabolism at Northwestern University Feinberg School of Medicine, said in a press release.

In normal biology, DNA sequences representing genes are translated into matching RNA molecules. These RNA molecules are then transcribed into functioning proteins.

But cells also have small RNA molecules, such as miRNAs, that do not originate proteins. Their function is to prevent other, larger RNA molecules from producing functional proteins. Once this discovery was made, small RNA molecules such as siRNAs and shRNAs were developed as a tool to study gene function. But one issue that has plagued studies with siRNAs or shRNAs is their non-specific, off-target effects.

However, researchers have now discovered that some of these off-target effects may be a mechanism conserved by evolution to ward off disease.

They found that 0ver 80% of tested siRNAs and shRNAs that target two specific, but related, proteins — CD95 and CD95 ligand (CD95L) — can induce cell death by simultaneously turning off several pro-survival genes. These pro-survival genes are often activated in cancer cells, which makes this an attractive new way to treat cancer.

Through a series of technical, yet elegant, experiments, the researchers show that the cancer cell death induced by the si/shRNA molecules is unrelated to the ability of these small RNA molecules to target and decrease expression of CD95 or CD95L. Thus, this cell death is an off-target effect of small RNA molecules.

The authors also noted that the cell death induced by many of these si/shRNAs evoked a similar biological response, suggesting that the off-target effect triggers a specific biological response. To define this biological response, the authors profiled cell lines treated with some of these si/shRNAs for changes in gene expression. They found that many of the genes affected are highly expressed in cancer and are critical for the survival of cancer cells.

These results suggest that in response to specific small RNA molecules, cells are dying because certain critical survival genes were being silenced. The authors called this type of cell death DISE, short for “death induced by survival gene elimination.”

The authors also showed that they can predict which shRNAs will have off-target effects that impact survival genes. In other words, they could predict the toxicity index of small RNA molecules. Such knowledge is useful and could be used to treat cancer. Future work is already underway to use this new knowledge to treat cancers in animal models.