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Abstract
Peroxiredoxin 6 (Prdx6) is the only member of 1-Cys subfamily of peroxiredoxins in human cells. It is the only Prdx acting on phospholipid hydroperoxides possessing two additional sites with phospholipase A2 (PLA2) and lysophosphatidylcholine-acyl transferase (LPCAT) activities. There are contrasting reports on the roles and mechanisms of multifunctional Prdx6 in several pathologies and on its sensitivity to, and influence on, the redox environment. We have down-regulated Prdx6 with specific siRNA in hepatoblastoma HepG2 cells to study its role in cell proliferation, redox homeostasis, and metabolic programming. Cell proliferation and cell number decreased while cell volume increased; import of glucose and nucleotide biosynthesis also diminished while polyamines, phospholipids, and most glycolipids increased. A proteomic quantitative analysis suggested changes in membrane arrangement and vesicle trafficking as well as redox changes in enzymes of carbon and glutathione metabolism, pentose-phosphate pathway, citrate cycle, fatty acid metabolism, biosynthesis of aminoacids, and Glycolysis/Gluconeogenesis. Specific redox changes in Hexokinase-2 (HK2), Prdx6, intracellular chloride ion channel-1 (CLIC1), PEP-carboxykinase-2 (PCK2), and 3-phosphoglycerate dehydrogenase (PHGDH) are compatible with the metabolic remodeling toward a predominant gluconeogenic flow from aminoacids with diversion at 3-phospohglycerate toward serine and other biosynthetic pathways thereon and with cell cycle arrest at G1/S transition.
Highlights
Peroxiredoxins (Prdx) are ubiquitous, abundant, and highly conserved enzymes whose main function is to catalyze the reduction of peroxides, taking part in the antioxidant battle of cells againstROS
We have found that the cells respond to Peroxiredoxin 6 (Prdx6) silencing by adapting carbon and lipid metabolism and by modulating signaling pathways to stop cell cycle progression at the G1/S
The nuclear size is an important parameter governing entry into the cell cycle. These results suggest cell cycle blockade induced by Prdx6 down-regulation
Summary
Peroxiredoxins (Prdx) are ubiquitous, abundant, and highly conserved enzymes whose main function is to catalyze the reduction of peroxides, taking part in the antioxidant battle of cells against. They all possess a catalytic or “peroxidatic” Cys residue that acts as a hydrogen donor to the peroxide substrate and have been classified in six subfamilies, of which three are present in mammalian cells [1]. They have a second “resolving” Cys that plays a critical role in the catalytic cycle and is reduced by thioredoxin (Trx). Human Prdx belongs to the “1-Cys” subfamily, which, unlike the other members of the Prdx family, does not possess a “resolving Cys” and may substitute Trx. Antioxidants 2019, 8, 505; doi:10.3390/antiox8110505 www.mdpi.com/journal/antioxidants. Mouse and human Prdx have an additional non-conserved Cys residue (Cys in human) with a so far unknown function
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