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Murine cytotoxic activated macrophages inhibit aconitase in tumor cells. Inhibition involves the iron-sulfur prosthetic group and is reversible.
Open accessAbstract
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.
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Cited by
Nitric oxide: A cytotoxic activated macrophage effector molecule
Hibbs, J. B., Taintor, R. R., Vavrin, Z., & Rachlin, E. M. (1988) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(88)80015-9 · Cited by 2,030
Self-citationStuehr, D. J., & Nathan, C. F. (1989) · The Journal of Experimental Medicine · doi:10.1084/jem.169.5.1543 · Cited by 1,744
Macrophage cytotoxicity: role for L-arginine deiminase and imino nitrogen oxidation to nitrite
Hibbs, J. B., Taintor, R. R., & Vavrin, Z. (1987) · Science · doi:10.1126/science.2432665 · Cited by 1,527
Self-citationRole of nitric oxide synthesis in macrophage antimicrobial activity
Nathan, C. F., & Hibbs, J. B. (1991) · Current Opinion in Immunology · doi:10.1016/0952-7915(91)90079-g · Cited by 1,523
Self-citationCleeter, M. W. J., Cooper, J. M., Darley-Usmar, V. M., Moncada, S., & Schapira, A. H. V. (1994) · FEBS Letters · doi:10.1016/0014-5793(94)00424-2 · Cited by 1,241
Metadata
- Authors
- Drapier, J. C., & Hibbs, J. B.
- Venue
- Journal of Clinical Investigation
- Published
- 1986-09-01
- Volume
- 78
- Issue
- 3
- Pages
- 790-797
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W1983880247
- Cited by
- 410
- References
- 0
- FWCI
- 2.21
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Drapier, J. C., & Hibbs, J. B. (1986). Murine cytotoxic activated macrophages inhibit aconitase in tumor cells. Inhibition involves the iron-sulfur prosthetic group and is reversible. Journal of Clinical Investigation. https://doi.org/10.1172/jci112642
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