Sirtuins, aging and cancer
The connection of sirtuin proteins with the development of breast cancer is explained
LifeSciencesToday by Vanderbilt University Medical Center:
Protein related to aging holds breast cancer clues
A new study led by Associate Professor David Gius of the Vanderbilt-Ingram Cancer Center shows how a deficiency of the aging-related Sirt3 protein can lay the foundation for the development of breast cancer in older women.
The results of the work (Randa Tao et al., Sirt3-Mediated Deacetylation of Evolutionarily Conserved Lysine 122 Regulates MnSOD Activity in Response to Stress), published in the journal Molecular Cell, provide information that can help screening, as well as prevention and treatment of this common disease.
Cancer is a disease associated with aging, and most of its cases occur in people over 50 years of age. However, the underlying biological processes are unclear.
"The link between aging and cancer is one of the most well–established facts in the field of cancer research," explains Dr. Gaius.
In the late 90s, proteins called sirtuins were associated with an increase in the life expectancy of animals kept on a diet with a limited number of calories. Scientists have concluded that sirtuins protect cells from damage that occurs during aging.
Sirtuins are found in all living organisms, including humans, who have 7 different types of these proteins.
"When sirtuins were discovered, it became obvious that there could be a mechanistic link between the genes that determine life expectancy and cancer," says Gaius.
Previously, Gaius and his colleagues created mice that lacked some of the sirtuins. In January last year, in the journal Cancer Cell, they reported that when Sirt3 – sirtuin, located in the mitochondria – is turned off, mice develop ER/PR-positive breast tumors, the most common type of breast cancer in postmenopausal women.
Moreover, these tumors showed elevated levels of free radicals and reactive oxygen species (ROS), including superoxide, the primary metabolite of oxygen in mitochondria. These facts provided an important clue to how Sirt3 deficiency can contribute to the development of such tumors.
"The mechanism, at least partially, of the development of receptor-positive breast cancer in such mice is a change in the levels of mitochondrial ROS, including superoxide," Gaius believes.
But how the absence of a gene associated with longevity leads to an increase in ROS levels remained unclear.
Since superoxide is usually removed from the cell by the enzyme manganese superoxide dismutase (MnSOD), Gaius suggested that Sirt3 deficiency may be associated with improper regulation of MnSOD.
In the present study, scientists have shown that mice with Sirt3 knockout have reduced MnSOD activity, despite the normal level of this enzyme.
Gaius and his colleagues found that the MnSOD enzyme in mice with the Sirt3 gene knocked out was abnormally modified by an acetyl group in a certain amino acid (lysine 122).
This aberrant modification of MnSOD reduces the enzyme's ability to detoxify and probably explains the increase in ROS levels in tumors of mice with Sirt3 knocked out.
"The results suggest that the aberrant regulation of MnSOD plays a role in the development of receptor-positive breast cancer," Dr. Gaius is confident.
Gaius and his colleagues have developed an antibody capable of assessing the status of MnSOD acetylation, which, in their opinion, can be used for "screening breast tissue samples to determine which women are at risk of developing (receptor-positive) cancer or the risk of its recurrence due to a violation of MnSOD regulation."
In addition, substances targeted by acetylation of these amino acids in MnSOD may be useful as chemopreventive agents for women at risk of developing and relapsing these cancers, the scientist notes.
The study was funded by grants from the National Cancer Institute and the Department of Defense of the United States.
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31.01.2011