ROCHESTER, Minn. -- Mayo Clinic researchers are the first to identify an interaction between two cellular proteins -- Skp2 and FOXO1 -- that is important for the growth and survival of cancer cells. Researchers also show that this interaction can be chemically reversed to stop cancer tumor growth -- a strategy that may lead to new and better cancer treatments.
Their report appears as an electronic advance article of PNAS, the Proceedings of the National Academy of Sciences ( http://www.pnas.org/cgi/reprint/102/5/1649). The research was performed on human cells in the laboratory and was found effective against human cancer cells. Researchers say it will be at least a year before the discovery can be applied in a human clinical trial.
For the first time, the Mayo Clinic research group provides laboratory evidence to describe a new mechanism by which cells lose the protection of tumor suppressors -- and therefore become vulnerable to cancerous cell growth. In particular, they show that Skp2 is the cellular player that interacts with FOXO1 by tagging it for destruction. This degradation of FOXO1 by high levels of Skp2, in turn, abolishes the ability of FOXO1 to suppress tumors. The result of their experiment indicates that human prostate cancer grows without the protection of the tumor suppressor protein FOXO1. Importantly, they also show that this loss of function can be reversed -- even in the presence of high levels of Skp2, by using chemicals that inhibit protein destruction, and thus block Skp2's action against FOXO1.
Significance of the Finding
"The major finding of our studies is that the tumor suppression function of FOXO1 is abolished due to Skp2-mediated protein degradation," says Haojie Huang, Ph.D., the urology researcher who performed the study. Co-investigator Donald J. Tindall, Ph.D., adds, "We've discovered a viable therapeutic target in human cancers, especially those with high levels of Skp2."
The Mayo Clinic researchers' findings suggest a promising new treatment target at which drug designers can aim new therapies for prostate cancer, as well as a number of other human cancers in which elevated levels of Skp2 have already been documented. These include cancers of the breast, lymphatic leukemia, small cell lung cancer and certain cancers of the mouth and colorectal cancer.
About Prostate Cancer
Prostate cancer is the second most common cause of cancer in men (skin cancer is first) and the second leading cause of cancer death in American men, exceeded only by lung cancer. In 2005, the American Cancer Society estimates 232,000 new cases will be diagnosed. While one in six men will be diagnosed with prostate cancer in his lifetime, only one in 33 will die of it. Because of the widespread disability and death that prostate cancer causes, finding new strategies to develop better treatments is an important public health goal.
The Mayo Clinic researchers wanted to understand the relationship between a group of proteins known as tumor suppressors that belong to the FOXO1 family, and the Skp2 protein. When tumor suppressors fail, the result is abnormal cell growth that can eventually transform healthy cells into cancerous cells. In particular, the Mayo Clinic team wanted to find out what disables FOXO1 tumor suppressor, and how it works -- in hopes of reversing the process to find a new cancer therapy strategy.
The Mayo Clinic research team knew from previous research:
* FOXO1 possesses tumor suppressor functions. Its tumor suppression works two ways: by curbing cell reproduction and by inducing cells to kill themselves -- especially cancer cells. * Some tumor suppressors lose their effectiveness through a means known as the "ubiquitin pathway." This pathway is a cellular strategy for attaching an identifying marker to the tumor suppressor that targets it for destruction. * Skp2 is known to target several tumor suppressors for destruction. * FOXO1 is suited to being targeted for destruction via the ubiquitin pathway.
The researchers noted that high levels of Skp2 were associated with low levels of FOXO1 in many human cancer cells, including prostate cancer -- and then combined the lines of evidence outlined above to design experiments to answer the specific question: Do elevated levels of Skp2 drive down and disable FOXO1, thus resulting in loss of its tumor suppression ability? The answer is yes.
Collaboration and Support
Other researchers who contributed to the study include Kevin Regan; Fang Wang, Ph.D.; Diping Wang; David Smith, Ph.D.; and Jan van Deursen, Ph.D. Their work was supported by the National Institutes of Health and T.J. Martell Foundation.
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