The researchers, led by Kimmel Cancer Center director Richard Pestell, M.D., Ph.D., hope the newly found connection will aid in better understanding the development of prostate cancer and lead to new drugs against the disease.
SIRT1 is a member of a family of enzymes called sirtuins that have far-reaching influence in all organisms, including roles in metabolism, gene expression and aging.
“We know that sirtuins play a role in aging, and that the risk for prostate cancer increases with aging, but no one has ever linked the two until now,” says Dr. Pestell, who is also professor and chair of cancer biology at Jefferson Medical College.
“We’ve shown that by making a prostate cancer with cells overexpressing a mutation for the androgen receptor, which is resistant to current forms of therapy, we can almost completely block the growth of these cells with SIRT1,” he says. Dr. Pestell and his team report their findings in November in the journal Molecular and Cellular Biology.
According to Dr. Pestell, prostate cancer cells can express a mutation that makes patients resistant to current forms of treatment such as hormonal therapy. Such therapy focuses on inactivating the androgen receptor by giving agents that shut off testosterone production.
In one experiment, the scientists took a series of mutations in androgen receptors from prostate cancer patients who are resistant to hormonal therapy and showed that SIRT1 blocks receptor activity, halting cancer growth. “We systematically tested each androgen receptor mutation,” Dr. Pestell explains. “These mutant receptors are resistant to current therapies and are all blocked by expression of SIRT1,” adding that prostate specific antigen (PSA) levels were used to confirm this. Rising PSA levels are frequently an indication of prostate cancer growth or recurrence, whereas falling levels indicate tumor shrinkage.
“This study shows that there is potentially new opportunity for these cancer patients with drugs that regulate SIRT1,” Dr. Pestell says.
“The discovery is a true breakthrough in our field,” says Chawnshang Chang, Ph.D., George Hoyt Whipple Professor of Pathology and Laboratory Medicine and professor of urology and of biochemistry at the University of Rochester.
Dr. Pestell and his co-workers also found a single amino acid within the androgen receptor that reacts with SIRT1’s enzymatic activity and proved in the laboratory that it was key to its cancer-halting effect. The work could lead to a model for drug screening, Dr. Pestell notes.
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