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Enhancing Mitochondrial Function Could Counteract Resistance to RT

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According to an international team of researchers, the resistance of some cancers to the cell-killing effects of radiation therapy (RT) could be a result of the irregularities in the mitochondria, the cellular structures responsible for generating energy.

The team’s findings were published in the journal, Developmental Cell.

Associate professor of biochemistry and molecular genetics at the University of Illinois at Chicago, Maxim Frolov and peers explored the effects of a metamorphosis in a gene called E2F, which controls other genes responsible for instigating programmed cell death, a normal function in most cells. Cells undergo programmed cell death, or apoptosis, when they are no longer required, as a normal process of aging, or in response to environmental factors like radiation that damage cellular DNA.

When Frolov and colleagues subjected fruit flies carrying a mutant E2F gene to radiation, genes that initiate apoptosis were activated, but the flies did not die.

"Something else was preventing the flies from dying, even though the genes needed to undergo cell death were turned on," said Frolov.

A more in-depth look within the cells of the flies showed that their mitochondria were distorted and generated less energy than normal mitochondria. Flies with the most severely misshapen mitochondria were the most resistant to radiation-induced cell death.

The observation in fruit flies suggested a previously unknown role for the E2F transcription factor, the protein encoded by E2F that regulates expression of other genes, in mitochondrial function.mitchondria rt

"It seems their mitochondria were also affected by the E2F mutation and were not functioning at full strength. You need properly functioning mitochondria to carry out programmed cell death,” said Frolov.

Observing human cells, the researchers found the same effects: those that lacked the E2F gene were resistant to the effects of radiation. Frolov noted that the similarity in the findings demonstrates that basic cellular functions do not change much across the vast evolutionary distance between fruit flies and humans.

"This result highlights a remarkable degree of conservation between fruit flies and humans and illustrates the advantages of using model organisms in cancer research," said Frolov, whose laboratory is part of the UIC Cancer Center.

Frolov and his colleagues believe that dysfunctional mitochondria might trigger the differences in how patients respond to radiation therapy. Prior studies have suggested that the inability of some patients' mitochondria to support apoptosis might be the cause for differences in their response to chemotherapy for acute myelogenous leukemia.

"If we could develop a small-molecule drug that could enhance mitochondrial function in these patients, we may be able to improve the effectiveness of radiation therapy," he said.

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