"Using genetic deletion we found that SIRT1 normally restrains prostatic intraepithelial neoplasia in animals. Therefore too little SIRT1 may be involved in the cellular processes that starts human prostate cancer," said Dr. Richard Pestell, M.D., Ph.D., MBA, executive Vice President of Thomas Jefferson University and Director of the Sidney Kimmel Cancer Center. “As we had shown that gene therapy based re expression of SIRT1 can block human prostate cancer tumor growth, and SIRT1 is an enzyme which can be targeted, this may be an important new target for prostate cancer prevention.” The researchers led by Dr. Pestell, created a mouse model that lacked SIRT1 and noticed that these mice were more likely to develop an early form of prostate cancer called prostatic intraepithelial neoplasia (PIN).
Other researchers had shown that SIRT1 can defend the cell against damage from free radicals. Pestell’s group took the work further by showing that in this prostate cancer model, free radicals built up in cells lacking SIRT1. They showed that normally, SIRT1 proteins help activate a mitochondrial protein called SOD2, in turn activating those proteins to keep free-radical levels in check. When SIRT1 level are diminished, SOD2 is no longer effective at removing free radicals, allowing a dangerous build up in the cells, and leading to PIN.
“The next step,” says first author Gabriele DiSante, Ph.D., a postdoctoral fellow in the department of Cell Biology at Jefferson, “is to determine if this is also important in the development of human prostate cancer.”
This work was supported in part by awards from the National Institutes of Health R01CA70896, R01CA75503 and R01CA86072. Work conducted at the Sidney Kimmel Cancer Center was supported by the NIH Cancer Center Core grant P30CA56036. This project was partially supported by the China Scholarship Council. This project is funded in part by the Pennsylvania Department of Health grant. The Department specifically disclaims responsibility for any analyses, interpretations or conclusions.
The authors declare no conflicts of interest.For more information, contact Edyta Zielinska, 215-955-5291, [email protected]. About Jefferson — Health is all we do.Thomas Jefferson University, Thomas Jefferson University Hospitals and Jefferson University Physicians are partners in providing the highest-quality, compassionate clinical care for patients, educating the health professionals of tomorrow, and discovering new treatments and therapies that will define the future of healthcare. Thomas Jefferson University enrolls more than 3,600 future physicians, scientists and healthcare professionals in the Sidney Kimmel Medical College (SKMC); Jefferson Schools of Health Professions, Nursing, Pharmacy, Population Health; and the Graduate School of Biomedical Sciences, and is home of the National Cancer Institute (NCI)-designated Sidney Kimmel Cancer Center. Jefferson University Physicians is a multi-specialty physician practice consisting of over 650 SKMC full-time faculty. Thomas Jefferson University Hospitals is the largest freestanding academic medical center in Philadelphia. Services are provided at five locations — Thomas Jefferson University Hospital and Jefferson Hospital for Neuroscience in Center City Philadelphia; Methodist Hospital in South Philadelphia; Jefferson at the Navy Yard; and Jefferson at Voorhees in South Jersey.
Article reference: G. Di Sante et al., “Loss of SIRT1 Promotes Prostatic Intraepithelial Neoplasia, Reduces Mitophagy and Delays PARK2 Translocation to Mitochondria,” Am J Pathol., 2014.
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