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Circadian clock and cancer progression linked

This from UNC:

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 in the Feb. 2, 2009 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.

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