Increased Protein Kinase A Activity Induces Fibrolamellar Hepatocellular Carcinoma Features Independent of DNAJB1.

Autor:	Shirani M; Laboratory of Cellular Biophysics, The Rockefeller University, New York, New York., Levin S; Laboratory of Cellular Biophysics, The Rockefeller University, New York, New York., Shebl B; Laboratory of Cellular Biophysics, The Rockefeller University, New York, New York., Requena D; Laboratory of Cellular Biophysics, The Rockefeller University, New York, New York., Finkelstein TM; Laboratory of Cellular Biophysics, The Rockefeller University, New York, New York., Johnson DS; Laboratory of Cellular Biophysics, The Rockefeller University, New York, New York.; Department of Physics and Astronomy, Hofstra University, Hempstead, New York., Ng D; Laboratory of Cellular Biophysics, The Rockefeller University, New York, New York., Lalazar G; Laboratory of Cellular Biophysics, The Rockefeller University, New York, New York., Heissel S; Proteomics Resource Center, The Rockefeller University, New York, New York., Hojrup P; Department of Biochemistry and Molecular Biology. University of Southern Denmark, Odense, Denmark., Molina H; Proteomics Resource Center, The Rockefeller University, New York, New York., de Jong YP; Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York.; Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, New York., Rice CM; Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York., Singhi AD; Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania., Torbenson MS; Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota., Coffino P; Laboratory of Cellular Biophysics, The Rockefeller University, New York, New York., Lyons B; Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico., Simon SM; Laboratory of Cellular Biophysics, The Rockefeller University, New York, New York.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2024 Aug 15; Vol. 84 (16), pp. 2626-2644.
DOI:	10.1158/0008-5472.CAN-23-4110
Abstrakt:	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. (©2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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