In cells, self-destructive behavior suggests strategy for fighting cancer

SOMETIMES, TO SURVIVE, our cells destroy their own ribonucleic acid (RNA), the part of our genetic instruction code that helps turn genes into proteins. Cells do this as part of the first line of defense against pathogens and damage. New research suggests how this mechanism could form the basis of a strategy against cancer.

The mechanism is part of the body’s innate immune system, which kicks into gear minutes after infection. The innate immune system holds pathogens at bay for the critical few days needed to make antibodies.

One of the mysterious weapons in the innate immune system is an enzyme called RNase L that chops up strands of RNA, an intermediate step between genes and their final products, proteins. Because viruses lack the machinery to make copies of themselves to spread infection, they hijack a cell’s reproductive technology and force it to make viral RNA and proteins. To fight back, the body sends RNase L. (The “ase” is a common ending for enzymes, and the “L” is for latent, because RNase L lies in wait for infection or damage signals.)

RNase L chops up the viral RNA, but it also shears the body’s own RNA. This self-mutilation is necessary for good health. Mice that lack RNase L are obese, diabetic and have signs of inflammation.

“This cleavage of the cell’s own RNA has a protective function. It does not always kill the cell, but when it does it eliminates only damaged or infected cells, which repairs the tissue. It ultimately means animals survive better,” said Alexei Korennykh, an associate professor of molecular biology. His lab was the first to solve the crystal structure of human RNase L, a result they published in the journal Science March 14, 2014.

Korennykh’s research is funded by the National Institutes of Health, the Sidney Kimmel Foundation, the Burroughs Wellcome Fund and the Vallee Foundation.

With the 3-D structure in hand, Korennykh and his team turned to the question of how RNase L works. Korennykh wondered if RNase L chops up every RNA that comes along, or just certain ones. To find out, the researchers sequenced every piece of RNA made in a typical human cell and evaluated them to see which ones were susceptible to RNase L.

What they found surprised them. RNase L chops up RNA strands that govern the rapid division of cells, as well as how well cells stick to each other. These two activities — when cells proliferate and attach themselves in new locations — are two of the key steps in the spread of cancer. They published the findings Dec. 29, 2015, in the Proceedings of the National Academy of Sciences.

The link between RNase L and cancer made sense because RNase L mutations are common in individuals from families with a hereditary predisposition for prostate cancer, Korennykh said. The team is exploring how to turn this discovery into a strategy for inhibiting cancer’s spread using small drug-like molecules to boost RNase L’s activity against cell proliferation and attachment.

“We really stumbled on this approach very unexpectedly,” Korennykh said. “Often the best experiments are the ones where you didn’t get the results you expected.” –By Catherine Zandonella