Intracellular dissemination of peroxidative stress. Internalization, transport, and lethal targeting of a cholesterol hydroperoxide species by sterol carrier protein-2-overexpressing hepatoma cells. J Biol Chem 2006 Aug 18;281(33):23643-51
Date
06/15/2006Pubmed ID
16772292DOI
10.1074/jbc.M600744200Scopus ID
2-s2.0-33747651634 (requires institutional sign-in at Scopus site) 36 CitationsAbstract
Sterol carrier protein-2 (SCP-2) plays a crucial role in the trafficking and metabolism of cholesterol and other lipids in mammalian cells. Lipid hydroperoxides generated under oxidative stress conditions are relatively long-lived intermediates that damage cell membranes and play an important role in redox signaling. We hypothesized that SCP-2-facilitated translocation of lipid hydroperoxides in oxidatively stressed cells might enhance cytolethality if highly sensitive sites are targeted and detoxification capacity is insufficient. We tested this using a clone (SC2A) of rat hepatoma cells that overexpress mature immunodetectable SCP-2. When challenged with liposomal cholesterol-7alpha-hydroperoxide (7alpha-OOH), SC2A cells were found to be much more sensitive to viability loss than vector control (VC) counterparts. Correspondingly, SC2A cells imported [14C]7alpha-OOH more rapidly. The clones were equally sensitive to tert-butyl hydroperoxide, suggesting that the 7alpha-OOH effect was SCP-2-specific. Fluorescence intensity of the probes 2',7'-dichlorofluorescein and C11-BODIPY increased more rapidly in SC2A than VC cells after 7alpha-OOH exposure, consistent with more rapid internalization and oxidative turnover in the former. [14C]7alpha-OOH radioactivity accumulated much faster in SC2A mitochondria than in VC, whereas other subcellular fractions showed little rate difference. In keeping with this, 7alpha-OOH-stressed SC2A cells exhibited a faster loss of mitochondrial membrane potential and development of apoptosis. This is the first reported evidence that peroxidative stress damage can be selectively targeted and exacerbated by an intracellular lipid transfer protein.
Author List
Kriska T, Levchenko VV, Korytowski W, Atshaves BP, Schroeder F, Girotti AWAuthors
Albert Girotti PhD, MS Emeritus Professor in the Biochemistry department at Medical College of WisconsinTamas Kriska Research Scientist I in the Pharmacology and Toxicology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsBiological Transport
Carbon Radioisotopes
Carcinoma, Hepatocellular
Carrier Proteins
Cell Line, Tumor
Cholesterol
Clone Cells
Gene Targeting
Glutathione Peroxidase
Humans
Intracellular Fluid
Lipid Peroxides
Liver Neoplasms
Rats
Subcellular Fractions
