Mitochondrial chaperones may represent novel targets for developing anti-cancer drugs
Scientists at the National Cancer Institute (NCI) have found that a mitochondrial chaperone protein, TRAP1, may act indirectly as a tumor suppressor as well as a novel target for developing anti-cancer drugs. Chaperone proteins, such as TRAP1, help other proteins adapt to stress, but scientists are coming to appreciate that they have other functions as well, such as, in this case, affecting tumor development. It is known that some cancers express more TRAP1, while others, such as bladder and renal cancer, express little. The cancer development aspect was not the primary goal of the study, however, which was to determine the role TRAP1 played in regulating mitochondrial activity in the cell. The mitochondria’s main job is energy conversion within the cell. The study, headed by Len Neckers, Ph.D., of NCI’s Urologic Oncology Branch, appears online the week of April 1, 2013, in PNAS.
As part of this work, Neckers and his colleagues developed human cell lines in which TRAP1 was not expressed. They then used these cell lines, as well as cells from laboratory mice, to study mitochondrial metabolism. They determined that TRAP1 regulates the balance between mitochondrial respiration and glycolysis, processes which help break down elements in the cell to produce energy. They found excess expression of TRAP1 directly suppressed mitochondrial respiration and indirectly increased glycolysis, while reduced TRAP1 expression had the opposite effect. Ultimately, the ability of TRAP1 to modulate mitochondrial metabolism affected both the way the cells produced energy and synthesis of nucleic acids, proteins and lipids. The scientists noted that cells with reduced TRAP1 were hyperenergetic—and were much more invasive compared to the same cells with excess TRAP1 expression. As a result of their findings, the scientists believe that pharmacologic targeting of mitochondrial chaperones, such as TRAP1, may represent a novel strategy to alter how cells utilize nutrients to make energy and cellular building blocks. Further, as a consequence of TRAP1’s effect on nutrient metabolism and energy production, it appears that TRAP1 also may play an unexpected, but important, role in controlling cancer metastasis.