Citations 2
Increased Protein Kinase A Activity Induces Fibrolamellar Hepatocellular Carcinoma Features Independent of DNAJB1
Shirani, Mahsa , Levin, Solomon , Shebl, Bassem , Requena, David , Finkelstein, Tova M. , Johnson, Daniel S. , Ng, Denise , Heissel, Søren , Højrup, Peter , Molina, Henrik , Rice, Charles M. , Lyons, Barbara A. , Simon, Sanford M. , Lalazar, Gadi , Heissel, Søren , Hojrup, Peter , Molina, Henrik , de Jong, Ype P , Rice, Charles M , Singhi, Aatur Dilip , Torbenson, Michael S , Coffino, Philip , Lyons, Barbara , Simon, Sanford M , Requena, David , Levin, Solomon N , Jong, Ype P. de , Torbenson, Michael
Cancer Research | June 18, 2024 | Volume: 84 | Issue: 16 | Pages: 2626-2644
Abstract Fibrolamellar hepatocellular carcinoma (FLC) is a rare liver cancer that is driven by the fusion of DNAJB1 and PRKACA, the catalytic subunit of protein kinase A (PKA). PKA activity is controlled through regulatory proteins that both inhibit catalytic activity and control localization, and an excess of regulatory subunits ensures PRKACA activity is inhibited. Here, we found an increase in the ratio of catalytic to regulatory units in FLC patient tumors driven by DNAJB1::PRKACA using mass spectrometry, biochemistry, and immunofluorescence, with increased nuclear localization of the kinase. Overexpression of DNAJB1::PRKACA, ATP1B1::PRKACA, or PRKACA, but not catalytically inactive kinase, caused similar transcriptomic changes in primary human hepatocytes, recapitulating the changes observed in FLC. Consistently, tumors in patients missing a regulatory subunit or harboring an ATP1B1::PRKACA fusion were indistinguishable from FLC based on the histopathological, transcriptomic, and drug–response profiles. Together, these findings indicate that the DNAJB1 domain of DNAJB1::PRKACA is not required for FLC. Instead, changes in PKA activity and localization determine the FLC phenotype. Significance: Alterations leading to unconstrained protein kinase A signaling, regardless of the presence or absence of PRKACA fusions, drive the phenotypes of fibrolamellar hepatocellular carcinoma, reshaping understanding of the pathogenesis of this rare liver cancer.
Disruption of proteome by an oncogenic fusion kinase alters metabolism in fibrolamellar hepatocellular carcinoma
Levin, Solomon , Tomasini, Michael D. , Knox, James , Shirani, Mahsa , Shebl, Bassem , Requena, David , Clark, Jackson, Heissel, Søren , Alwaseem, Hanan , Surjan, Rodrigo C. , Lahasky, Ron, Molina, Henrik , Lyons, Barbara A. , Migler, Rachael D. , Levin, Solomon N , Surjan, Rodrigo , Torbenson, Michael S , Lyons, Barbara , Migler, Rachael D , Coffino, Philip , Simon, Sanford M , Requena, David , Torbenson, Michael , Simon, Sanford M.
Science Advances | June 21, 2023 | Volume: 9 | Issue: 25 | Pages: No page available
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.