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Researchers Isolate Key Part of Cells’ ‘Death’ Signals

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BOSTON – Scientists at Dana-Farber Cancer Institute have located the key part of cellular “death proteins” that can induce cancer cells to commit suicide. The investigators speculate that these peptides potentially could serve as a model for future cancer drugs that could be more potent and less toxic than those used now.

In the cover article of the September issue of Cancer Cell, researchers reported that these natural-born killers – peptide subunits of cell-signaling “BH3” proteins – could out-maneuver opposing “anti-death” proteins and trigger the suicide process. Cell suicide or “apoptosis” prevents wayward cells from growing out of control and becoming cancerous.

“Many cancer cells may stay alive due to the overexpression of anti-death proteins,” said Dana-Farber’s Anthony Letai, MD, PhD, lead author of the paper. “That we could specifically target a key death signal associated with cancer gives hope that the same can ultimately be done to cancer cells in people as well.”

Stanley Korsmeyer, MD, is senior author of the paper. Korsmeyer, who is a Howard Hughes Medical Institute investigator at Dana-Farber, and his laboratory colleagues have previously been the source of major advances in understanding the body’s elaborate mechanism for programmed cell death.

The interaction of several “die” or “survive” signals from inside and outside the cell ultimately determine whether cells continue to reproduce or are terminated. Proteins carry these signals and the relative balance of the survival and apoptotic (“death”) signals determines the cell’s fate.

The new findings, which emerged from laboratory experiments on cell components, are another step in unraveling the body’s extraordinarily complicated system of apoptosis, also known as “programmed cell death.”

Apoptosis, which culls out cells during fetal development after they have served their purpose, also helps prevent cancer by killing off cells that have become damaged and which threaten to grow out of control to form tumors. Certain infection-fighting immune cells also are marked for apoptotic death after a brief active life so that they don’t turn their weapons on the body’s normal cells.

A “family” of apoptosis-regulating proteins contains both pro-death (including BAK, BIM and BID) and pro-survival members. One pro-survival molecule is called BCL-2, named for the disease it causes – B-Cell lymphoma – when it is overexpressed in white blood cells, allowing them to accumulate abnormally. BCL-2 performs much of its pro-survival function by binding and sequestering pro-death molecules, preventing them from transmitting a pro-death signal.

Some pro- and anti-apoptosis molecules are generally found on the membrane forming the outside of mitochondria. These are tiny mini-organs in cells that provide energy but also contain a substance that kills cells if it is released into the cell’s interior.

One of the crucial signals for apoptosis is a protein called BAK, which resides in an inactive form on the mitochrondrial membrane. When other pro-death signals activate it, BAK changes shape and opens holes in the membrane that release the lethal cytochrome c from the mitochondrion. The pro-survival signal BCL-2 also is found on the membrane, and its function is to keep BAK inactive, preventing cell suicide.

Letai, who is also an instructor in medicine at Harvard Medical School, and his colleagues looked closely at the life-death process by isolating living mitochondria from cells and manipulating them in the laboratory. They devised tests that could show whether molecules like BAK were “activated” – that is, carrying out their pro-death function.

BAK can be set into motion in two ways: pro-death signal proteins BID or BIM can bind to BAK, or other pro-death proteins BAD and BIK can flood BCL-2, keeping that pro-survival protein occupied so that BID proteins can evade BCL-2 and bind to BAK, turning it on.

Letai’s research group stripped the two kinds of pro-death proteins down to a basic unit, called a peptide, that enables them to bind to other molecule. Experiments showed that these peptides could hit their targets – BCL-2 or BAK – and set cell death in motion.

“Interestingly, they come in two ‘flavors’,” said Korsmeyer, who also is the Sidney Farber Professor of Pathology at Harvard Medical School. “Those that can activate the killers (‘BID-like’ peptides) and those that sensitize a cell to dying by blocking the BCL-2 molecules that are trying to keep the cells alive (‘BAD-like’ peptides).” Since dependence for survival on overexpressed BCL-2 is likely to be restricted mainly to cancer cells, Korsmeyer says that the ‘BAD-like’ peptides are promising prototypes for a low-toxicity anti-cancer drug that would not damage normal cells.

With these peptides in hand, researchers may be able to manipulate the apoptosis mechanism to halt cancers by sentencing the cells to death. Future work will focus on optimizing the behavior of the peptides, said the scientists, as well as testing candidate molecules in their assay systems for BCL-2 inactivation.

“Our peptides are not cancer drugs yet, but they are prototypes for how drugs using this strategy should behave.” Letai said.

The paper’s coauthors are Michael C. Bassik, Loren Walensky, MD, PhD, Mia D. Sorcinelli, and Solly Weiler, PhD, all of Dana-Farber.

The study was funded in part by the National Institutes of Health, the Claudia Adams Barr Society and the American Society of Hematology. Letai is a Leukemia and Lymphoma Society Scholar.

Dana-Farber Cancer Institute (www.dana-farber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.

An animation is available on the Cancer Cell web site, www.cancercell.org/cgi/content/full/2/3/183/DC1

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