Scientists from Maryland and New Jersey have identified a molecularpathway in mice that makes prostate cells vulnerable to cancer-causingoxygen damage. The pathway, which is also involved in human prostatecancer, may help determine how and whether antioxidants, such ascertain vitamins or their products that reverse the damage, can preventprostate cancer.
The researchers, from Johns Hopkins Kimmel Cancer Center and TheCancer Institute of New Jersey, found that when the tumor suppressorgene Nkx3.1 malfunctions, prostate cells lose the ability to protectthemselves from oxygen damage. Results of the new studies are in theAugust issue of the journal Cancer Research.
"Normally, cells with functioning Nkx3.1 seem to processoxidative free radicals appropriately," says Theodore L. DeWeese, M.D.,a co-author of the study and director of the Department of RadiationOncology & Molecular Radiation Sciences at Hopkins. "But cells withfaulty Nkx3.1 genes cannot manage oxidative injury. Then, their DNAgets damaged, and that leads to other mutations that in turn can bringabout cancer."
The researchers specifically found that a key role ofNkx3.1 is to prevent oxidative damage by regulating the expression ofother genes. Oxygen causes cellular degeneration through so-calledoxidative free radicals --- highly reactive atoms with an unpairedelectron that can rip through cells like a bullet. Free radicals areproduced as a result of normal body metabolism, and are widely known tobe intimately involved in aging, as well as cancer development.
"Our findings provide new insights regarding therelationship between loss of protection against oxidative stress andthe initiation of prostate cancer," adds Cory Abate-Shen, Ph.D., seniorstudy author and professor of medicine and neuroscience, member at theCenter for Biotechnology and Medicine at UMDNJ-Robert Wood JohnsonMedical School. "One key finding is that defects in the oxidativeresponse pathway occur early in prostate cancer development."Abate-Shen also is co-director of the Prostate Cancer Program at theCancer Institute of New Jersey.
For the study, the researchers used a sophisticated computertechnique called gene expression profiling to compare in-depth thegenetic makeup of mice whose Nkx3.1 gene was disrupted with that ofnormal mice. The method takes all DNA from the cells and allowsscientists to look for aberrations. DeWeese likens it to studyingthousands of pages of an encyclopedia simultaneously; trying toidentify what pages may have been altered.
They observed that mice with malfunctioning Nkx3.1 incorrectlyexpressed 638 genes, including those that created a significantreduction in some antioxidant enzymes vital to oxidative damageprevention. These alterations occurred in mice as early as four monthsof age - well before cellular changes are visible in the mouseprostate. The mutant mice also displayed a fivefold increase in theamount of cancer-related DNA damage, called8-hydroxy-2'-deoxyguanosine.
Further investigation showed that the progression toprostate cancer as it occurs in mice lacking Nkx3.1 and another tumorsuppressor, Pten, correlated with additional deregulation ofantioxidants and more profound accumulations of oxidative damage to DNAand protein.
"Mice with defective Nkx3.1 provide a valuable tool forpreclinical studies to test whether antioxidants might be useful forprostate cancer prevention," Abate-Shen says and continuing studieswill test antioxidants or other agents on the altered mice.
Prostate cancer is the most commonly diagnosed cancer in menand ranks second to lung cancer as the leading cause of cancer deathamong American men. More than 232,000 cases of prostate cancer arediagnosed and treated annually in the United States, and close to30,000 men die each year of the disease. Most men over the age of 50will have some experience with prostate disease -- with either anenlarged prostate or cancer.
The study was supportedby the National Institutes of Health. Co-authors were Xuesong Ouyang ofUMDNJ-Robert Wood Johnson Medical School, and William G. Nelson ofHopkins.
Johns Hopkins Kimmel Cancer Centerhttp://www.hopkinskimmelcancercenter.org
The Cancer Institute of New Jerseyhttp://www.cinj.org/
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