Two new studies provide stunning evidence suggesting that cyclin D1 – which is found in up to eight times normal amounts in half of all breast cancers – can cause a shift in the cancer cell's metabolism, changing its focus from energy production to proliferation. The findings, they say, may point to new therapeutic strategies against cancer.
Reporting last month in the journal Molecular and Cellular Biology, Kimmel Cancer Center director Richard G. Pestell, M.D., Ph.D., Professor and Chair of the Department of Cancer Biology at Jefferson Medical College, and colleagues showed for the first time that cyclin D1 – normally involved in promoting cell division – inhibits the size and activity of the cell's energy-making mitochondria.
In a separate report in August in the Proceedings of the National Academy of Sciences (PNAS), Dr. Pestell and a different team identified the mechanism behind cyclin D1's mitochondrial takeover. The research, taken together, shows that the inhibition leads to increased proliferation of cancer cells.
"From the cancer cell's point of view, the inhibition allows the cell to shift its biosynthetic priorities – it allows it to shift from making mitochondria themselves to synthesizing DNA and making the cell proliferate," says Dr. Pestell.
"Cyclin D1 shifts the individual cell's metabolism away from making mitochondria and towards cellular proliferation and the various genes involved in promoting such proliferation," he says.
The mitochondria often are called the "powerhouse" of the cell because they produce about 90 percent of the body's energy. They are located in the cytoplasm outside of each cell's nucleus.
Dr. Pestell notes that scientists have long suspected a link between mitochondrial malfunction and cancer, and since 1930 have known about such a change in metabolism when the cell turns cancerous. But the mechanisms haven't been well understood. When cells turn cancerous, they shift the way they metabolize glucose and other substrates. The researchers believe that their findings about cyclin D1 are part of such a mechanism. "These changes were observed previously," he says. "Now we know that the same factor that is involved in causing breast cancer also directly causes a metabolic shift."
I. Bernard Weinstein, M.D., Frode Jensen Professor of Medicine at Columbia University, notes that the 1930 discovery that the function of mitochondria is often impaired in cancer cells has remained unexplained and cancer research has been mainly focused on abnormalities in the function of genes in the nucleus of cells. The work by Dr. Pestell's group "provides novel insights into how these two types of abnormalities in cancer cells might be related."
In the PNAS publication, Dr. Pestell's team found that a protein, nuclear respiratory factor-1 (NRF-1), regulates a gene called mtTFA and is essential for mitochondrial
function. To make mitochondria, then, NRF-1 turns on mtTFA, which then activates genes that produce mitochondria. Cyclin D1 inactivates NRF-1, halting production.
"This discovery advances our understanding of the behavior of cancer cells and may suggest new types of cancer therapy," Dr. Weinstein says.
Dr. Pestell notes that such metabolic changes should leave the cancer cell vulnerable. "We'd like to link that change in metabolism to therapies," he says. "We've been able to prove that we can see changes in metabolism in the breast, and we should be able to target that change and kill the cancerous cells." He explains that specialists can image tumors based on changes in metabolism.
The results could also "provide a mechanism for targeting the mitochondria, rather than the nucleus," he says, noting that cancer drugs usually target nuclear genes. "Importantly, they provide a direct link between the mitochondria and the nucleus – one gene regulating both compartments of the cell. We didn't know what coordinated both functions. This shows both are functionally linked by a common gene."
"If we have therapies that target changes in metabolism, it allows us to develop therapies selective for the cancerous cells only," says Dr. Pestell.
Steve Benowitz | EurekAlert!
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