Researchers in the Division of Radiation Biology may have taken a step toward solving the mystery of how some cancer cells resist DNA-damaging chemotherapy and radiation.
Many anticancer therapies aim to kill tumor cells by disrupting their DNA, throwing the cancer cells into a genetic chaos that quickly leads to their deaths. Unfortunately, some tumor cells develop resistance to these therapies by learning to repair the DNA damage rapidly, before it can kill the cell.
To understand how this happens, researchers are studying a bacterium with extraordinary DNA repair abilities of its own.
|Scanning electron micrograph of Deinococcus radiodurans (Original SEM image by Peggy A. O'Cain and Margaret C. Henk, Louisiana State University; modified by Peter Reid, The University of Edinburgh.)|
Deinococcus radiodurans has fascinated biologists since its discovery in 1956. Listed as the world’s toughest bacterium in the “Guinness Book of World Records,” it can withstand extreme, DNA-destroying factors such as dehydration, vacuum and acid. It can even survive 50 to 100 times the amount of radiation that would kill other bacteria. This ability to keep its DNA intact makes D. radiodurans an ideal model for studying resistance to DNA-damaging anticancer therapies because scientists believe cancer cells might use similar protective mechanisms.
In a study published online March 1 in the journal Molecular & Cellular Proteomics, division director Bing Shen, Ph.D., and Huiming Lu, Ph.D., visiting graduate student in the division, led a team that found that a protein called Pprl activates several DNA repair mechanisms in D. radiodurans following irradiation.
The team blasted two versions of the bacterium — one able to make Pprl normally and one with its Pprl “knocked out” — with enough gamma radiation to harm the bacteria cells but not kill them. They found that the bacteria with normal Pprl responded immediately by increasing production of 31 different proteins. Levels of these proteins remained unchanged in the bacteria that could not make Pprl.
Many of the 31 proteins are known to be involved with DNA damage response and repair or other important processes within the bacteria.
The researchers also found that the normal bacteria decreased production of five other proteins while the knock-out bacteria showed no change.
While human cells have no known protein like Pprl, Shen and the team hopes the study will guide them to similar mechanisms in human tumor cells that might lead to radiation resistance as well as resistance to other DNA-damaging therapies.
“Radiation resistance in tumor cells is a major impediment to therapy,” he said. “If we can find how cancer cells become resistant and block the mechanism, we could see a strong improvement in outcomes for patients.” The research project was funded by the U.S. Department of Defense’s Advanced Molecular Medicine Initiative program led at City of Hope by Richard Jove, Ph.D., director of Beckman Research Institute.