Contact: Leslie Lang
[email protected]
919-966-9366
University of North Carolina School of Medicine
UNC study: Tinkering with the circadian clock can suppress cancer growth
CHAPEL HILL – Researchers at the
University of North Carolina at Chapel Hill have shown that disruption
of the circadian clock – the internal time-keeping mechanism that keeps
the body running on a 24-hour cycle – can slow the progression of
cancer.
The study disputes some of the most recent research
in the field indicating that alteration of this daily cycle predisposes
humans and mice to cancer. The UNC researchers found that genetically
altering one of four essential "clock" genes actually suppressed cancer
growth in a mouse model commonly used to investigate cancer. The
findings could enable clinicians to reset the internal clock of each
cancer cell to render it more vulnerable to attack with
chemotherapeutic drugs.
"Adjusting the clock in this way
could certainly be a new target for cancer treatment," said senior
study author Aziz Sancar, M.D., Ph.D., a member of the UNC Lineberger
Comprehensive Cancer Center and Sarah Graham Kenan Professor of
Biochemistry and Biophysics in the UNC School of Medicine. Sancar is
also a member of the National Academy of Sciences, the Turkish Academy
of Sciences and the American Academy of Arts and Sciences.
"Our
study indicates that interfering with the function of these clock genes
in cancer tissue may be an effective way to kill cancer cells and could
be a way to improve upon traditional chemotherapy," Sancar said. His
findings appear February 2, 2009 in the online early edition of the
Proceedings of the National Academy of Sciences.
Previous
research has shown that the disruption of the body's natural circadian
rhythms affects people's health. One of the largest epidemiological
studies ever performed, the Nurses' Health Study, found that nurses who
worked the night shift had a higher incidence of breast cancer than
those who worked days. Another study of flight attendants whose
internal biological clocks had been wrecked by travel on transatlantic
flights produced similar findings.
Yet when scientists, including Sancar, began to tinker with the
molecular mechanisms within the internal clocks of animal models, they
did not always see such an effect. Circadian rhythms in humans and in
mice are controlled by "clock genes," four of which are absolutely
essential. In a study four years ago, Sancar found that deleting the
clock gene cryptochrome in mice did not increase the incidence of
cancer as had previously been expected.
While altering the clock gene did not cause cancer in otherwise
normal mice, Sancar and his colleagues wanted to see if it would
accelerate the development of tumors in a mouse model that is already
predisposed to cancer. Therefore, in this study they modified the
cryptochrome gene in mice that also had defects in a gene called P53,
which is mutated in nearly half of human cancers. The researchers found
that disturbing the internal clock in these mice did not speed up the
onset of cancer, but instead had the opposite effect – it extended
their lives by 50 percent.
The researchers then wanted to
know how interfering with the cryptochrome gene had reduced the
incidence of cancer. By closely examining the series of biological
events in the disease's development, they determined that the mutation
of this clock gene reactivates the intracellular signals that can
eliminate cancerous cells. Sancar said this tactic essentially makes
cancer cells more likely to commit cell suicide – through a process
known as apoptosis – in response to the stresses of UV radiation or
chemotherapy.
"These results suggest that altering the function of this clock
gene, at least in the 50 percent of human cancers associated with p53
mutations, may slow the progression of cancer," Sancar said. "In
combination with other approaches to cancer treatment, this method may
one day be used to increase the success rate of remission."
The research was supported by the National Institutes of
Health. Study co-authors from Sancar's UNC laboratory include the lead
author and postdoctoral fellow Nuri Ozturk, Ph.D.; Jin Hyup Lee, a
graduate student; and postdoctoral fellow Shobhan Gaddemeedhi, Ph.D.
The
study follows the recent publication earlier this month of another
paper from Sancar's laboratory in the Proceedings of the National
Academy of Sciences. It suggested that chemotherapy treatment for
cancer is most effective at certain times of day because that is when a
particular enzyme system – one that can reverse the actions of
chemotherapeutic drugs – is at its lowest levels in the body.
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To read the news release about the previous study, go to: http://uncnews.unc.edu/news/health-and-medicine/unc-study-supports-role-of-circadian-clock-in-response-to-chemotherapy.html
School of Medicine contact: Les Lang, (919) 966-9366, [email protected]
Lineberger contact: Dianne Shaw, (919) 966-7834, [email protected]
News Services contact: Patric Lane (919) 962-8596, [email protected]