Dolezal 2017 J Biol Chem
| Dolezal JM, Wang H, Kulkarni S, Jackson L, Lu J, Ranganathan S, Goetzman ES, Bharathi SS, Beezhold K, Byersdorfer CA, Prochownik EV (2017) Sequential adaptive changes in a c-Myc-driven model of hepatocellular carcinoma. J Biol Chem 292:10068-86. |
Dolezal JM, Wang H, Kulkarni S, Jackson L, Lu J, Ranganathan S, Goetzman ES, Bharathi SS, Beezhold K, Byersdorfer CA, Prochownik EV (2017) J Biol Chem
Abstract: Hepatocellular carcinoma (HCC) is a common cancer that frequently overexpresses the c-Myc (Myc) oncoprotein. Using a mouse model of Myc-induced HCC, we studied the metabolic, biochemical, and molecular changes accompanying HCC progression, regression, and recurrence. These involved altered rates of pyruvate and fatty acid Ξ²-oxidation and the likely re-directing of glutamine into biosynthetic rather than energy-generating pathways. Initial tumors also showed reduced mitochondrial mass and differential contributions of electron transport chain complexes I and II to respiration. The uncoupling of complex II's electron transport function from its succinate dehydrogenase activity also suggested a mechanism by which Myc generates reactive oxygen species. RNA sequence studies revealed an orderly progression of transcriptional changes involving pathways pertinent to DNA damage repair, cell cycle progression, insulin-like growth factor signaling, innate immunity, and further metabolic re-programming. Only a subset of functions deregulated in initial tumors was similarly deregulated in recurrent tumors thereby indicating that the latter can "normalize" some behaviors to suit their needs. An interactive and freely available software tool was developed to allow continued analyses of these and other transcriptional profiles. Collectively, these studies define the metabolic, biochemical, and molecular events accompanying HCC evolution, regression, and recurrence in the absence of any potentially confounding therapies.
Β© 2017 by The American Society for Biochemistry and Molecular Biology, Inc. β’ Keywords: Yes-associated protein (YAP), Energy metabolism, Glycolysis, Hepatocellular carcinoma, Ξ²-catenin β’ Bioblast editor: Plangger M β’ O2k-Network Lab: US PA Pittsburgh Goetzman ES
Labels: MiParea: Respiration
Pathology: Cancer
Organism: Mouse Tissue;cell: Liver Preparation: Intact cells Enzyme: TCA cycle and matrix dehydrogenases
Coupling state: LEAK, OXPHOS Pathway: N, S, NS HRR: Oxygraph-2k
Labels, 2019-08
