A new kill code embedded in each cell to extinguish cancer

A new kill code embedded in each cell to extinguish cancer

A kill code is embedded in every cell in the body whose function may be to cause the self-destruction of cells that become cancerous, reports a new study. As soon as the cell's inner bodyguards sense it is mutating into cancer, they punch in the kill code to extinguish the mutating cell.

The code is embedded in large protein-coding ribonucleic acids (RNAs) and in small RNAs, called microRNAs, which scientists estimate evolved more than 800 million years ago in part to protect the body from cancer. The toxic small RNA molecules also are triggered by chemotherapy, scientists report.

Cancer can't adapt or become resistant to the toxic RNAs, making it a potentially bulletproof treatment if the kill code can be synthetically duplicated. The inability of cancer cells to develop resistance to the molecules is a first, the scientists said.

"Now that we know the kill code, we can trigger the mechanism without having to use chemotherapy and without messing with the genome. We can use these small RNAs directly, introduce them into cells and trigger the kill switch," said lead author.

Chemotherapy has numerous side effects, some of which cause secondary cancers, because it attacks and alters the genome, the author said. "We found weapons that are downstream of chemotherapy," the lead author noted.

The paper describing the kill code and identifying how the cancer-fighting microRNAs use the code to kill tumor cells will be published in Nature Communications. The paper describing that protein-coding large RNAs can be converted into toxic small RNAs was published in eLife.

"My goal was not to come up with a new artificial toxic substance," the lead author said. "I wanted to follow nature's lead. I want to utilize a mechanism that nature developed."

In the first of the new studies, the authors tested all 4,096 different combinations of nucleotide bases in the 6mers until they found the most toxic combination, which happens to be G-rich, and discovered microRNAs expressed in the body to fight cancer use this 6mer to kill cancer cells.

Toxicity of these siRNAs stems from targeting survival genes with C-rich 3′UTRs. The master tumor suppressor miRNA miR-34a-5p is toxic through such a G-rich 6mer seed and is upregulated in cells subjected to genotoxic stress.

An analysis of all mature miRNAs suggests that during evolution most miRNAs evolved to avoid guanine at the 5′ end of the 6mer seed sequence of the guide strand. In contrast, for certain tumor-suppressive miRNAs the guide strand contains a G-rich toxic 6mer seed, presumably to eliminate cancer cells.

In the second new study, the authors showed the cells chop a gene (Fas ligand) involved in cancer cell growth into small pieces that then act like microRNAs and are highly toxic to cancer. The group found about three percent of all protein-coding large RNAs in the genome can be processed in this way.

"Based on what we have learned in these two studies, we can now design artificial microRNAs that are much more powerful in killing cancer cells than even the ones developed by nature," the lead author said.

The next step? "We absolutely need to turn this into a novel form of therapy," the lead author said. They are exploring multiple ways to trigger the embedded kill code to kill cancer cells, but stressed a potential therapy is many years off.