TAMPA, Fla. (May 25, 2012) – Researchers from Moffitt Cancer Center have unraveled the biochemical mechanisms by which prostate cancer cells acquire resistance to radiotherapy, making the disease almost incurable.
Their study was published in a recent issue of The Journal of Biological Chemistry.
“Radiation therapy is the primary treatment choice for localized and aggressive prostate cancer,” said study lead author Nupam P. Mahajan, Ph.D., an assistant member at Moffitt and assistant professor at the University of South Florida. “However, resistance to radiation treatment is a major obstacle in treating this form of cancer. Radiotherapy resistance makes this type of prostate cancer very difficult to treat.”
According to Mahajan, the initial treatment in prostate cancer patients is to remove the circulating male hormones, testosterone, that “feed” prostate cancer. This treatment, called androgen deprivation therapy, has been the standard of care for aggressive prostate cancer. Unfortunately, in most cases the disease recurs after androgen deprivation therapy and reaches the stage of being radiotherapy resistant, where there is little hope for cure.
The molecular mechanisms by which prostate cancer cells acquire radioresistance have been unclear. However, medical research, particularly cancer research, has benefited from increased understanding of biochemical and molecular “signaling pathways” through which cells change their nature and function through what is called “signal transduction.” Signal transduction involves the binding of a protein molecule “messenger” (Ack1 protein in this case) to another protein molecule “receptor” (Androgen Receptor or AR) and then translocation of the complex to a distinct location in the cell called the nucleus. Once in the nucleus, the receptor activates expression of certain genes.
In this study, Mahajan and his colleagues found that there is a signaling “nexus” of three key players Ack1, AR and ATM (Ataxia Telangiectasia Mutated) that is critical for the growth and survival of prostate cancer cells that not only function despite low levels of androgen but also upon radiation treatment.
Further, the researchers discovered a small molecule inhibitor, a potential drug molecule that suppresses the signaling nexus of these three key players leading to radiosensitization of hormonally insensitive prostate cancer. Their data reveal for the first time the molecular basis by which Ack1 directly plays a role in creating radiation resistance in aggressive prostate cancer and Ack1 inhibitors could be used as potential drug for treatment of this cancer.
“The cross talk between the three reveals a previously unknown mechanism by which metastatic prostate cancer cells survive radiation therapy,” explained Mahajan. “Accordingly, therapy designed to resensitize the cells to radiation by inhibiting the action of Ack1 opens up therapeutic options for these patients. Inhibitors that can target the signaling pathways that confer radioresistance in specific tissues, such as the prostate, are urgently needed.”
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Located in Tampa, Moffitt Cancer Center is a National Cancer Institute-designated Comprehensive Cancer Center, which recognizes Moffitt’s excellence in research and contributions to clinical trials, prevention and cancer control. Moffitt is also a member of the National Comprehensive Cancer Network, a prestigious alliance of the country’s leading cancer centers, and is listed in U.S. News & World Report as one of “America’s Best Hospitals” for cancer.
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