Fabien Llambi, Ph.D., research lab specialist in the Immunology Department, and Doug Green, Ph.D., Chair of the Immunology Department.
Researchers at St. Jude Children’s Research Hospital have uncovered a new pathway for mitochondrial cell death that involves the protein BCL-2 ovarian killer, otherwise known as BOK. The discovery, which is described online in the journal Cell, may lead to new ways to trigger cell death in some types of cancer cells.
“The newly discovered mechanism for mitochondrial cell death is by the effector protein BOK, which is normally targeted for destruction at the endoplasmic reticulum,” said Doug Green, Ph.D., chair of the St. Jude Department of Immunology and the study’s corresponding author. “This pathway of molecular events appears to be intrinsically tied to the levels of stress experienced by the cell and ensures the rapid, programmed destruction of both the cell and its contents.”
Multicellular organisms employ cell death as a survival mechanism by removing infected, damaged or unwanted cells. Mitochondria are known as the energy-generating organelles of the cell. However, they may also activate cell death under certain conditions and assist in the removal of damaged cells from the body.
The mitochondrial pathway of cell death (apoptosis) starts by permeabilization of the mitochondrial outer membrane, which becomes peppered with small holes. The space between the inner and outer membranes of the mitochondria leaks proteins such as cytochrome c and other molecules into the cytosol. That activates caspase proteases and sets in motion a series of reactions leading to the cell’s rapid demise.
“BOK is an effector of mitochondrial apoptosis that appears to work in a different way to known proteins that initiate mitchondrial cell death,” said Fabien Llambi, Ph.D., research laboratory specialist in the St. Jude Department of Immunology and the paper’s first author. “The stability of BOK appears to be directly related to the amount of cellular stress experienced within the endoplasmic reticulum.”
The researchers revealed that BOK is controlled at the level of protein stability by components of the endoplasmic reticulum-associated degradation (ERAD) pathway. ERAD is a quality control mechanism that helps detect and eliminate damaged and often unfolded proteins.
The scientists were also able to show that BOK works independently of BAK and BAX, two other members of the BCL-2 family of proteins that regulate and contribute to mitochondrial cell death.
“The fate of the cell during stress appears to be intricately wired to the signaling pathways, such as the BOK pathway we have discovered, that trigger mitochondrial cell death,” Green said. “Our work also suggests that cancer cells expressing high levels of BOK may be particularly sensitive to inhibitors that target the proteasome or the ERAD pathway.”
By developing specific inhibitors that target the ERAD pathway, researchers could provide useful alternatives to some of the known proteasome inhibitors that stop the growth of cancer cells. Some proteasome inhibitors affect multiple targets in ways that do not meet the desired level of specificity. An ERAD inhibitor might overcome this drawback. Further work is needed to identify suitable protein targets that would be amenable to this type of interference.
The study’s other authors are Yue-Ming Wang, Bernadette Victor, Mao Yang, Desiree M. Schneider, Sébastien Gingras, Melissa J. Parsons, Janet H. Zheng, Scott A. Brown, Stéphane Pelletier, Tudor Moldoveanu and Taosheng Chen.
This research was supported by funding from the National Institutes of Health (grants GM 096208 and GM 110034) and ALSAC.
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