Study Provides More Evidence for a Central Role of Mitochondria in Apoptosis

(Philadelphia, PA) - Within the workings of a human cell there is an innate mechanism for self-destruction - a carefully choreographed act called apoptosis, or programmed cell death. Without apoptosis, diseased cells, especially cancerous cells, are not eliminated from the body and can continue to threaten other cells. Not surprisingly, cancer researchers are trying to piece together the mechanics of apoptosis and how they can use it against cancer cells.

In the June 15 issue of Genes and Development, researchers from the University of Pennsylvania School of Medicine identify the essential role of two pro-apoptotic proteins, Bax and Bak, in initiating apoptosis.

This new work demonstrates that cells lacking Bax and Bak cannot be killed by either chemotherapy or irradiation. It also demonstrates conclusively what scientists have suspected for several years: that chemotherapy and irradiation work to treat cancer by tricking the cancer cell into committing suicide. This study is the third of a series of articles that researchers have published in recent months exploring the functional role of the Bcl-2 family of proteins - of which Bax and Bak are members - in regulating cell death.

"Within the Bcl-2 family of proteins, some proteins are actively pro-apoptotic while others are anti-apoptotic," said Craig B. Thompson, M.D., scientific director of the Abramson Family Cancer Research Institute at the Penn Cancer Center. "The result is a careful balance where one set of the proteins prevents the other from working."

In this new report Thompson and his colleagues demonstrate that this balancing act takes place on the surface of a cell's mitochondrion, which is the cellular organ devoted to converting sugars and fats into usable energy for the cell. In cells that lack Bak and Bax, the researchers demonstrate that virtually all forms of cell death are eliminated. Without Bax or Bak to turn off the function of the mitochondria, cells become immortal.

"Although we have known that damaged mitochondria can initiate apoptosis, the importance of mitochondria in this process has become a central issue," said Thompson. "We believe the new evidence demonstrates that the mitochondria plays a major role in all forms of apoptosis. This has important implications for the development of new cancer treatments as well as provides new hope that cell death can be prevented during a stroke or heart attack."

It is Bax and Bak, however, that are essential in carrying out the disruption of mitochondria. Interestingly, Bax and Bak are also redundant, as either protein - by itself - is effective in triggering apoptosis. According to Thompson, the redundant role of Bax and Bak represents a previously unknown but essential step in regulating apoptosis. "The fact that we have two separate proteins that do the same essential job stresses the importance of this step in controlling cell survival," said Thompson.

Bax and Bak also illustrate the overall complexity of the mechanism behind apoptosis. But by examining how individual parts of the mechanism function, the researchers hope to map out new ways to correct for the mechanism when it fails.

"To look at it broadly, there are only two major types of diseases: ones where cells are killed and ones where cells refuse to die," said Thompson. "Cancer is one of the latter - it occurs when diseased cells that do not respond to apoptotic signals grow out of control. The trick is to find a way to get cancer cells to respond to those signals."

Contributors to this research include Wei-Xing Zong, PhD, and Tullia Lindsten, PhD, of the Abramson Family Cancer Research Institute at Penn and Andrea J. Ross, PhD. and Grant R. MacGregor, PhD., of the Center for Molecular Medicine at the Emory University of School of Medicine.

Their research has been funded by the National Institutes of Health and The Leonard and Madlyn Abramson Family Cancer Research Institute at the University of Pennsylvania Cancer Center.

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