Researchers at Children’s Hospital Boston have discovered the cellular target of angiostatin, the protein made famous a decade ago for its seemingly miraculous ability to cure cancer in mice. According to the paper, published online May 22 in Blood, angiostatin performs its myriad functions by interacting with proteins in mitochondria, small organelles that serve as the cell’s power generators.
Angiostatin was first discovered in 1994 by the late Judah Folkman as an anti-angiogenic protein in mice, blocking blood vessel formation in tumors and effectively starving them into remission. Since then, researchers have worked to elucidate angiostatin’s mechanism, hoping to learn enough to reproduce the same antitumor effects in humans. Unfortunately, although several proteins have been found to bind to angiostatin, a clear picture of how it works has yet to emerge.
One problem may simply be that researchers have been looking in the wrong place. In the latest study, led by first author Tong-Young Lee, a postdoctoral fellow in the Vascular Biology Program at Children’s, the researchers found that angiostatin binds to mitochondrial malate dehydrogenase, a protein involved in the crucial metabolic process known as the Krebs cycle. This may come as a surprise to some scientists, because until now, there had been little evidence of angiostatin’s direct involvement in mitochondria.
“Eight years ago I came across malate dehydrogenase as a major binding protein of angiostatin,” recalled Kashi Javaherian, senior author of the study, an HMS lecturer on surgery and a senior research associate in the Vascular Biology Program. “But it was so far-fetched at the time, I didn’t touch it.”
Now, the idea no longer seems far-fetched. By treating a variety of cell types with fluorescently labeled angiostatin and observing them under the microscope, Lee found that whenever a cell took up the protein into its cytoplasm, the angiostatin would appear as a fluorescent signal in the mitochondria. Furthermore, when Lee applied short interfering RNA to some cells to dampen production of another protein, ATP synthase, the cells displayed significantly lower levels of mitochondrial angiostatin. This fact, combined with previous observations that angiostatin binds ATP synthase on the outer cell membrane, led Lee and Javaherian to think that ATP synthase is at least partially involved in the process of transporting angiostatin from outside the cell into the mitochondria.
According to the researchers, the challenge now is to find out exactly how angiostatin makes its way to the mitochondria and to explore the potential of delivering anticancer drugs to the organelles.
“We think that the action is not so much on the cell surface,” said Javaherian. “Sure, [angiostatin] has to bind to the cell surface in order to go inside, but the main action takes place in mitochondria.”
Students may contact Kashi Javaherian at Kashi.Javaherian@childrens.harvard.edu for more information.
Conflict Disclosure: The authors declare no conflicts of interest.
Funding Sources: National Institutes of Health, National Aeronautics and Space Administration, Deutsche Forschungsgemeinschaft, Department of Defense, the Breast Cancer Research Foundation; the content of this work is the responsibility solely of the authors.
