The American Cancer Society has awarded WenYong Chen, Ph.D., assistant professor of cancer biology, a $540,000 grant to study how genes that can lengthen life are involved in prostate cancer. The research could pave the way for new preventive measures and therapies for the disease.
Researchers have shown that a gene called SIRT1, when active at high levels, can offer longer life to lower organisms such as yeast. Whether it can extend human life is unclear — and the subject of much study. Aside from the gene’s influence on longevity, scientists also know that SIRT1 is highly active in cancers.
 WenYong Chen (Photo by Darrin S. Joy) |
Chen wants to understand how SIRT1 is involved in cancer. The answer may lie in how cells get their energy.
Cells generate energy through a process called the tricarboxylic acid, or TCA, cycle. This process uses large amounts of a compound called nicotinamide adenine dinucleotide, or NAD. Because NAD is so important to energy production, cells quickly recycle — or salvage — it after use, so they can keep the energy-making process moving.
SIRT1 also uses NAD to do its job. Because cancer cells have high levels of SIRT1, they use large amounts of NAD. This means they must salvage NAD even more quickly than normal cells.
Chen is studying the enzymes that cancer cells use when salvaging NAD to trace back the process and understand how SIRT1 influences cancer.
“Enzymes that control NAD salvage should be critical to the function of SIRT1 in tumor cells,” he said. “In fact, we have found cancer cells make more of these enzymes.”
Chen chose to study these enzymes and their genes in prostate cancer cells, specifically, because they are most active in this cancer type. “They are hugely overexpressed as compared to other cancers,” said Chen. “We’re not sure why; that’s another point of our research.”
In addition, prostate cancer cells generate energy differently from other cancer cells. Most prostate cancers arise from a specific cell type that lines the prostate gland. These cells normally secrete large amounts of citrate, a key compound in the TCA cycle, to make prostatic fluid. Because these cells must pump out citrate, they cannot use it to make energy. Instead of depending on the TCA cycle, they use a process called glycolysis. When the cells turn cancerous, however, they stop excreting citrate and instead restart the TCA cycle to make energy.
“This is the opposite of other cancers,” said Chen. Other cancers shut down the TCA cycle and use glycolysis to get energy from blood sugar.
Because the TCA cycle occurs in mitochondria, the cell’s powerhouses, and because a number of other genes related to SIRT1 are found only in mitochondria, Chen saw what could be a unique opportunity to study these genes and their roles in forming cancer.
“We want to understand how SIRT1 and its related genes control energy production in mitochondria and how that affects carcinogenesis,” Chen said. “In other words, what controls activation of mitochondria during tumorigenesis in prostate cancer cells?”
Added Chen: “If you know how this is regulated, you can certainly modulate SIRT1 activity to prevent or treat prostate cancer.”
