Researchers Isolate Protein Domain Linked to Tumor Progression
When a promising cancer drug reached clinical trials in the
1990s, researchers were disappointed by the debilitating side
effects that limited the trials. The drug inhibited a family of
enzymes known as matrix metalloproteinases (MMPs). Now,
researchers at Rensselaer Polytechnic Institute have shown that
creating drugs that inactivate a different part of the MMP
enzyme could have the capacity to target the tumor without the
damaging side effects. Their findings, which hold promise for
improved cancer therapies, were published Feb. 5 in the online
Early Edition of the Proceedings of the National Academy of
Sciences (PNAS).
“The failure of the clinical trials suggest that the
proteinases were not only involved in the pathology of the
disease, but also in maintaining the normal health of the
patient,” said Andrea Page-McCaw, assistant professor of
biology at Rensselaer and the corresponding author of the
study. Page-McCaw and her colleagues, including senior research
specialist Bernadette M. Glasheen and undergraduate biology
student Aasish Kabra, set out to determine the functions of
different parts of an MMP enzyme. These parts, known as
domains, usually correlate to a specific protein function.
Inactivating one domain within a protein can often have
significant and unknown consequences.
To determine MMP domain function, the researchers used a
simple model organism, the common fruit fly. Unlike mouse and
other mammal models that have 24 or more different and
semi-redundant MMPs, the fly model has only two. This
substantially simplifies the problem of understanding function
of each domain, as there aren’t so many other closely related
proteins that can fill in if a domain on one is
broken.
The researchers found that a domain known as the hemopexin
domain was important for tissue invasion events. During tissue
invasion, cells from one tissue invade into and usually move
through another tissue, sometimes ending up in a completely
different part of the body from where the tissue was formed.
This pathway is similar to metastasis, where cancer cells
spread from the original tumor to other sites in the body. Fly
larvae missing the hemopexin domain of Mmp1 had highly
distorted or absent head and wings. The growth of such body
parts requires tissue invasion to move the cells to the right
place in the animal. These abnormalities indicate that a
hemopexin domain is needed for tissue invasion in fly
development, and possibly in cancer metastasis, according to
Page-McCaw.
The other primary domain in MMPs, the catalytic domain, is
considered the business part of the enzyme, as it is where MMPs
break up or destroy other proteins. The catalytic domain was
extensively targeted by pharmaceutical companies in efforts to
block MMP function in cancer. The researchers found that
in flies, like in patients, blocking or removing the catalytic
domain caused many different kinds of problems, beyond simply
failures of tissue invasion. When the catalytic domain was
removed, the larvae could not grow normally because they were
unable to make necessary and basic developmental changes in
their exoskeletons. The findings shed light on why inhibiting
the catalytic domain in the drug trials would have both the
favorable impact of stopping tissue invasion and unfavorable
impact of significant side effects. In the future, inhibiting
only the hemopexin domain could be a method to inhibit tissue
invasion without inhibiting all other necessary MMP functions,
Page-McCaw said.
The research was funded by the National Institutes of Health
(NIH) and the March of Dimes.
Published
February 17,
2009 |
Contact: Gabrielle DeMarco
Phone: (518) 276-6542
E-mail: demarg@rpi.edu |
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