May 4, 2005

Keeping Cancer in Check:
Penn Researchers Demonstrate that a Metabolic Enzyme Works Through the Tumor-Suppressor Protein p53
to Control Cellular Replication

(Philadelphia, PA) - Researchers at the University of Pennsylvania School of Medicine have identified in normal cells that a common metabolic enzyme, which acts as a rheostat of cellular conditions, also controls cell replication. This control is managed through p53, the much-studied protein implicated in many types of cancer. The discovery of the interaction between these two molecules may lead to new ways to fight cancer. First author Russell G. Jones, PhD, a postdoctoral fellow in the laboratory of senior author Craig Thompson, MD, at the Abramson Family Cancer Research Institute at Penn, and colleagues describe their findings in the most recent issue of Molecular Cell.

This work tests the novel notion that cancer cells co-opt cellular pathways that govern metabolism in order to proliferate beyond a cell’s normal means. Cancer cells have, by definition, a high metabolic rate and consume glucose at a high rate. One of the fundamental questions being tested in the Thompson lab is the importance of metabolism in cancer and investigating how cancer cells differ from normal cells, allowing them to survive and replicate. (Thompson is the Chair of Penn’s Department of Cancer Biology and Scientific Director of the Abramson Family Cancer Research Institute.)

“We think that the enzyme interprets the energetic environment of the cell,” explains Jones. “It senses the stress a cell sees - such as low oxygen, low glucose, or the presence of free radicals - and, from this, can induce a check on replication through p53, acting in effect as a tumor-suppressor.”

For this study, the investigators looked at noncancerous mouse cells called fibroblasts to see how normal cells work and what they do physiologically when faced with an environmental challenge: in this case, low glucose levels, explains Jones.

When the enzyme - called AMP-activated protein kinase (AMPK) - is turned on, it prevents cells from replicating. It acts as a sensor to detect energy levels in a cell. When the cell experiences energy-limiting conditions, which is typified by low glucose, it uses more energy than it produces and enters into an energy-deficit state. In essence, AMPK acts as a “fuel gauge,” letting a cell know when glucose levels are dangerously low. When AMPK is activated by low glucose levels, it stops cells from replicating.

But how is p53 implicated? Normally p53 is activated in response to stress, and it stops a cell from replicating through a complicated set of biochemical steps. For example, if a cell is hit by radiation, enzymes called kinases activate p53, leading to inhibition of cell replication. “We found that cells without p53 due to a mutation would continue to proliferate under low glucose conditions, bypassing the AMPK checkpoint,” says Jones. The lab is now doing follow-up studies and is finding that when AMPK is activated in a tumor cell that has no active p53, it still proliferates, escaping the AMPK checkpoint. This avenue of study may one day provide another approach to treating cancer, the researchers surmise.

The study was funded in part by the National Institutes of Health. Study co-authors are David R. Plas, Sara Kubek, and Monica Buzzai from Penn, as well as Morris J. Birnbaum and James Mu from the Howard Hughes Medical Institute at Penn, and Yang Xu from the University of California, San Diego.

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The Abramson Cancer Center of the University of Pennsylvania was established in 1973 as a center of excellence in cancer research, patient care, education and outreach. Today, the Abramson Cancer Center ranks as one of the nation’s best in cancer care, according to U.S. News & World Report, and is one of the top five in National Cancer Institute (NCI) funding. It is one of only 39 NCI-designated comprehensive cancer centers in the United States. Home to one of the largest clinical and research programs in the world, the Abramson Cancer Center of the University of Pennsylvania has 275 active cancer researchers and 250 Penn physicians involved in cancer prevention, diagnosis and treatment.

PENN Medicine is a $2.7 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System.

Penn’s School of Medicine is ranked #3 in the nation for receipt of NIH research funds; and ranked #4 in the nation in U.S. News & World Report’s most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

Penn Health System is comprised of: its flagship hospital, the Hospital of the University of Pennsylvania, consistently rated one of the nation’s “Honor Roll” hospitals by U.S. News & World Report; Pennsylvania Hospital, the nation's first hospital; Presbyterian Medical Center; a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home health care and hospice.