Why understanding metabolism matters

Chris, thank you very much. The production of NADPH via citrate could be a mechanism to limit ROS within survivable bounds for cancer cells. We've hypothesized that overproduction of UCP2 may play a similar role. Metabolic cancer inhibition by ketone bodies, however, shouldn't be affected by the NADPH mechanism unless cancers employing this mechanism also don't over-express UCP2. Our 7 cancer lines all over-express UCP2, but others may not. Pre-testing of cancer lines before attempting ketogenic therapies may help identify cancers most likely to respond.

Gene, do you think this could be helpful. It was published just a few days ago: "If you think of ROS as fire, then NADPH is like the water used by cancer cells to douse the flames," Dr. DeBerardinis said. But how could NADPH from the PPP help deal with the stress of ROS produced in a completely different part of the cell? "What we did was to discover how this happens," Dr. DeBerardinis said. The current study in Nature demonstrates that cancer cells use a "piggybacking" system to carry reducing equivalents from the PPP into the mitochondria. This movement involves an unusual reaction in the cytosol that transfers reducing equivalents from NADPH to a molecule called citrate, similar to a reversed reaction of the Krebs cycle, he said. The citrate then enters the mitochondria and stimulates another pathway that results in the release of reducing equivalents to produce NADPH right at the location of ROS creation, allowing the cancer cells to survive and grow without the benefit of matrix attachment. "We knew that both the PPP and Krebs cycle provide metabolic benefits to cancer cells. But we had no idea that they were linked in this unusual fashion," he said. "Strikingly, normal cells were unable to transport NADPH by this mechanism, and died as a result of the high ROS levels." http://www.nature.com/nature/journal/vaop/ncurrent/full/nature17393.html

Thanks for showing us that it's all about metabolism- the basic requirement of life and for opening our world to your exciting research. L.