A protein located on the membrane of a cell's energy source can block the signal that tells cells to die, according to a study by researchers at The University of Texas (UT) Southwestern Medical Center at Dallas. Discovery of the role of this protein in allowing cells to continue to multiply into tumors instead of breaking down in a normal manner could lead to more efficient cancer-fighting drugs.
Researchers found that BCL2, an integral protein on the outer membrane of mitochondria, a cell's principal energy source, prevents the release of an electron-carrier protein from the mitochondria. In healthy cells, an outflow of energy signals the beginning of apoptosis, or programmed cell death.
"We found that during apoptosis, the signal that comes out of mitochondria is a release of cytochrome c," said Xiaodong Wang, assistant professor of biochemistry at UT Southwestern and senior researcher on the study. "Cytochrome c is a small soluble protein that triggers the cell death program when it's released from the mitochondria."
Wang said his research team, which reported its findings in the February 21st issue of Science, discovered that an overabundance of BCL2 stops the release of cytochrome c, a carrier in the cell's energy chain.
Previously, scientists knew that BCL2 was a cancer-causing gene, but they didn't know why the protein allowed tumor growth. They also knew that cytochrme c was necessary for cell death to begin, but no one had found the connection between the two.
Using drugs administered in human chemotherapy treatment on cells in vitro, Wang and his team found that cells undergoing apoptosis had an elevation of cytochrome c outside the mitochondria. When they introduced an elevated amount of BCL2, cytochrome c was blocked from coming out of the mitochondria. Therefore, cell death did not begin.
Overabundance of BCL2 May Cause Resistance to Chemotherapy
Wang said one reason he took this approach in studying why cells do not die is that people going through chemotherapy build up a resistance to the cancer-fighting drugs because they have an overabundance of BCL2.
"By finding exactly how the BCL2 works, we might be able to find a way to bypass this problem," he said. "Theoretically this could be important for cancer treatment because someone might be able to find a drug that specifically targets the mitochondria."
The researchers now want to determine whether there are specific channels on the mitochondria membrane that control this cell activity and how the BCL2 protein influences these channels. They also want to figure out the mechanism by which BCL2 blocks the release of protein from mitochondria.
"It's very satisfactory for us to finally understand why a protein on the mitochondria can prevent cell death," Wang said. The other scientists involved in the study were UT Southwestern researcher Xue-song Liu and Emory University researchers Jie Yang, Kail Bhalla, Caryn Naekyung Kim, Ana Maria Ibrado, Jiyang Cai, Tsung-I Peng, and Dean P. Jones.
The study was partially funded by an American Cancer Society research grant.