Targeting Helpers of Heat Shock Proteins Could Help Treat Cancer, Cardiovascular Disease
News Jul 01, 2009
Dissecting how heat shock protein 90 gets steroid receptors into shape to use hormones like estrogen and testosterone could lead to targeted therapies for hormone-driven cancers, such as breast and prostate, that need them as well, Medical College of Georgia researchers say.
"We are trying to understand how Hsp90 folds steroid receptors into the proper conformation so they work," says Dr. Ahmed Chadli, biochemist in the MCG Center for Molecular Chaperones/Radiobiology and Cancer Virology. "The goal is to interfere with their function when they are helping cancer."
Hsp90 is vital to steroid receptors whether they are involved with normal hormonal function or cancer. Vital to Hsp90 are helpers such as p23 that help it dock at the receptor, and another Dr. Chadli discovered, GCUNC45, that helps stabilize Hsp90 at the receptor.
In fact, drugs that eventually target the helpers of Hsp90 may one day help physicians target cancer.
"Our hypothesis is that p23 and other co-chaperones helping Hsp90 are driving these hormone-driven cancers," Dr. Chadli says. "We think the Hsp90 machinery is an important piece of cancer development. Whatever we can do to modulate Hsp90 machinery, by targeting it directly or its helpers, is a good thing."
While every cell needs heat shock proteins, cancer cells need them even more to maintain their mutated, unstable and extremely busy proteins, he says. "The terminology we use is that the Hsp90 machinery is hijacked by cancer," says Dr. Chadli.
Proteins that enable cancer basics such as endless cell reproduction, securing a constant supply of blood and oxygen and ignoring signals to commit suicide, are all dependent on Hsp90. Experience with Hsp90 inhibitors already under study for cancer shows they tend to migrate to the highly active Hsp90 in tumors.
He wants to block Hsp90 in cancer cells by learning more about how it works in normal and cancer cells. A recent grant from the American Heart Association will enable him to further decipher how GCUNC45 interacts with Hsp90 and how that interaction affects steroid receptor function. "By understanding how these interactions are happening, we could modulate the function of the receptor, Hsp90 or both."
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