Disruption of proteome by an oncogenic fusion kinase alters metabolism in fibrolamellar hepatocellular carcinoma
Solomon Levin, Michael D. Tomasini, James Knox, Mahsa Shirani, Bassem Shebl, David Requena, Jackson Clark, Søren Heissel, Hanan Alwaseem, Rodrigo C. Surjan, Ron Lahasky, Henrik Molina, Michael Torbenson, Barbara A. Lyons, Rachael D. Migler, Philip Coffino, Sanford M. Simon
Abstract
Fibrolamellar hepatocellular carcinoma (FLC) is a usually lethal primary liver cancer driven by a somatic dysregulation of protein kinase A. We show that the proteome of FLC tumors is distinct from that of adjacent nontransformed tissue. These changes can account for some of the cell biological and pathological alterations in FLC cells, including their drug sensitivity and glycolysis. Hyperammonemic encephalopathy is a recurrent problem in these patients, and established treatments based on the assumption of liver failure are unsuccessful. We show that many of the enzymes that produce ammonia are increased and those that consume ammonia are decreased. We also demonstrate that the metabolites of these enzymes change as expected. Thus, hyperammonemic encephalopathy in FLC may require alternative therapeutics.