title: Murine cytotoxic activated macrophages inhibit aconitase in tumor cells. Inhibition involves the iron-sulfur prosthetic group and is reversible.
abstract: Previous studies show that cytotoxic activated macrophages cause inhibition of DNA synthesis, inhibition of mitochondrial respiration, and loss of intracellular iron from tumor cells. Here we examine aconitase, a citric acid cycle enzyme with a catalytically active iron-sulfur cluster, to determine if iron-sulfur clusters are targets for activated macrophage-induced iron removal. Results show that aconitase activity declines dramatically in target cells after 4 h of co-cultivation with activated macrophages. Aconitase inhibition occurs simultaneously with arrest of DNA synthesis, another early activated macrophage-induced metabolic change in target cells. Dithionite partially prevents activated macrophage induced aconitase inhibition. Furthermore, incubation of injured target cells in medium supplemented with ferrous ion plus a reducing agent causes near-complete reconstitution of aconitase activity. The results show that removal of a labile iron atom from the [4Fe-4S] cluster, by a cytotoxic activated macrophage-mediated mechanism, is causally related to aconitase inhibition.
mesh_terms: D000154:Aconitate Hydratase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002951:Citrates / Q000378:metabolism; D019343:Citric Acid; D004247:DNA / Q000096:biosynthesis; D004227:Dithionite / Q000494:pharmacology; D005260:Female; D005296:Ferrous Compounds / Q000494:pharmacology; D007501:Iron / Q000378:metabolism; D007506:Iron-Sulfur Proteins / Q000378:metabolism*; D007521:Isocitrate Dehydrogenase / Q000378:metabolism; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D008264:Macrophages / Q000502:physiology*; D008297:Male; D008667:Metalloproteins / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D009374:Neoplasms, Experimental / Q000201:enzymology*; D010101:Oxygen Consumption; D013053:Spectrophotometry
chemical_list: D002951:Citrates; D005296:Ferrous Compounds; D007506:Iron-Sulfur Proteins; D008070:Lipopolysaccharides; D008667:Metalloproteins; D004227:Dithionite; D019343:Citric Acid; D004247:DNA; D007501:Iron; D007521:Isocitrate Dehydrogenase; D000154:Aconitate Hydratase