Disrupting a metabolic pathway in the liver in a way that creates a more "cancer-like" metabolism actually reduces tumor formation in a mouse model of liver cancer. That's the surprising and potentially useful finding from a new UI study published recently in the journal Cell Reports.
The study, led by Eric Taylor, PhD, associate professor of biochemistry in the University of Iowa Carver College of Medicine, and first author Sean Tompkins, a UI graduate and medical student in Taylor's lab, shows that the mitochondrial pyruvate carrier (MPC), a protein complex that is critical for glucose production in the liver, may represent a new target for preventing liver cancer.
Liver cancer is the fifth most common cancer and the second leading cause of cancer death worldwide. Because factors that cause it, such as obesity and diabetes, are becoming more common, rates of liver cancer are rising.
Right now, non-alcoholic fatty liver disease, caused by obesity and diabetes, is the fastest growing cause of liver cancer in the developed world and no effective treatment exists. As result, prevention of NAFLD progression to liver cancer is the most effective way to prevent liver cancer deaths," Tompkins explains. "Our findings are significant because they show a way to change liver metabolism that may prevent liver cancer in high-risk humans."
Sean Tompkins, first author and graduate, University of Iowa
Previous work by the UI team had identified the MPC as a possible target for treating diabetes and non-alcoholic fatty liver disease, which are both risk factors for liver cancer. In the new study, the team used a mouse model of liver cancer to examine what happens in that disease when the MPC is turned off in the liver.
The researchers found that mice that were missing the MPC in liver cells developed two-thirds fewer tumors than control animals, and the tumors were smaller and more prone to cell death.
The results were surprising to Taylor because disrupting the MPC actually promotes a more cancer-like metabolism, with cells increasing their use of glucose and an amino acid called glutamine to produce energy.
"The first surprise is that an intervention resulting in cancer-like metabolism prevents cancer," says Taylor, who also is a member of the Fraternal Order of Eagles Diabetes Research Center and Holden Comprehensive Cancer Center at the UI. "The second surprise is why this likely happens and provides a new twist on our understanding of glutamine metabolism in cancer."
Cells use glutamine to make glutathione, a major cellular antioxidant that is important for cancer development and progression. The study suggests that disrupting the MPC reroutes glutamine into energy production and decreases the amount of glutathione the cells can produce. This loss of glutathione weakens the cancer cells' ability to withstand stress.
"Since glutathione is important for tumor defense against chemotherapy and oxidative damage, MPC inhibitors could have the potential to be used as adjuvant sensitizers for liver cancer chemo- and radiation therapy," Taylor says. "But it's critical to note that a tremendous amount of future research and testing will be required to understand the therapeutic value of MPC modulation in humans."
The new findings are particularly interesting because a molecule known to inhibit MPC activity is currently undergoing clinical trial testing in patients with a severe form of NAFLD called non-alcoholic steatohepatitis. Taylor notes that these trials could provide important information about the safety and therapeutic contribution of altering MPC activity in people.
Tompkins, S. C. et al. (2019) Disrupting Mitochondrial Pyruvate Uptake Directs Glutamine into the TCA Cycle away from Glutathione Synthesis and Impairs Hepatocellular Tumorigenesis. Cell Reports. doi.org/10.1016/j.celrep.2019.07.098.