Prostate cell regulating protein can transform healthy cells into
9 Dec 2010
A protein with an important role in the prostate has been found
to also cause cancer.
The protein, called Bmi-1, has a crucial role in regulating the self-renewal of normal
prostate stem cells. These are needed to repair injured cells or restore
normal cells killed by hormone withdrawal therapy for cancer. Bmi-1
has now been found to
aid the transformation of healthy cells into prostate cancer cells
researchers at the University of California at Los Angeles.
Bmi-1 is often up-regulated in prostate
cancer, has been associated with higher grade cancers and is
predictive of poor prognosis, according to previous studies.
However, its functional roles in prostate stem cell maintenance and
prostate cancer have been unclear, said Dr. Owen Witte, who is
director of the Broad Stem Cell Research Center, a Howard Hughes
Medical Institute investigator and senior author of the study.
A study of loss and gain of function in prostate stem cells
indicated that Bmi-1 expression was required for self-renewal
activity and maintenance of prostate stem cells with highly
proliferative abilities. Loss of Bmi-1 expression blocks the
self-renewal activity, protecting prostate cells from developing
abnormal growth changes which can lead to cancer.
More importantly, Bmi-1 inhibition slowed the growth of an
aggressive form of prostate cancer in animal models, in which the
PTEN tumor suppressor gene was removed allowing the cancer to run
wild, Witte said.
“We conclude by these results that Bmi-1 is a crucial regulator
of self-renewal in adult prostate cells and plays important roles in
prostate cancer initiation and progression,” Witte said. “It was
encouraging to see that inhibiting this protein slows the growth of
even a very aggressive prostate cancer, because that could give us
new ways to attack this disease.”
UCLA stem cell researchers have been studying the mechanisms of
prostate stem cells for years on the theory that the mechanism that
gives the cells their unique ability to self-renew somehow gets high
jacked by cancer cells, allowing the malignant cells to grow and
spread. If the mechanism for self-renewal could be understood,
researchers could find a way to interrupt it once it is taken over
by the cancer cells, Witte said.
Rita Lukacs, a doctoral student in Witte’s laboratory and first
author of the study, found that Bmi-1 inhibition also stops
excessive self-renewal driven by other pathways. This suggests that
the Bmi-1 pathway may be dominant to other genetic controls that
affect the cancer phenotype.
“Prostate cancer can be initiated by so many different mutations,
if we can find a key regulator of self-renewal, we can partially
control the growth of the cancer no matter what the mutation is,”
Lukacs said. “We’re attacking the process that allows the cancer
cells to grow indefinitely. This provides us an alternate way of
attacking the cancer by going to the core mechanism for cancer cell
self-renewal and proliferation.”
Witte said future work will be centred on searching for methods
to control these pathways in human prostate cancer cells.
The study was published in the early online edition of
the journal Cell Stem Cell.
Prostate cancer is the most frequently diagnosed non-skin cancer
and the second most common cause of cancer-related deaths in men.
This year alone, more than 277,000 men in the United States will be
diagnosed with prostate cancer. Of those, 32,000 men will die from
This study was funded by the California Institute for
Regenerative Medicine, Howard Hughes Medical Institute, Prostate
Cancer Foundation, Ovarian Cancer Research Fund, a Stewart and Lynda
Resnick Prostate Cancer Foundation Grant and a Stein/Oppenheimer
Clinical Translational Seed Grant.