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J. Biol. Chem., Vol. 281, Issue 33, 23643-23651, August 18, 2006

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Intracellular Dissemination of Peroxidative Stress

INTERNALIZATION, TRANSPORT, AND LETHAL TARGETING OF A CHOLESTEROL HYDROPEROXIDE SPECIES BY STEROL CARRIER PROTEIN-2-OVEREXPRESSING HEPATOMA CELLS^*

Tamas Kriska, Vladislav V. Levchenko, Witold Korytowski, Barbara P. Atshaves^¶, Friedhelm Schroeder^¶, and Albert W. Girotti¹

From the Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, Institute of Molecular Biology, Jagiellonian University, 31-120 Krakow, Poland, and ^¶Department of Physiology and Pharmacology, Texas A&M University, College Station, Texas 77843

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-7-hydroperoxide (7-OOH), SC2A cells were found to be much more sensitive to viability loss than vector control (VC) counterparts. Correspondingly, SC2A cells imported [¹⁴C]7-OOH more rapidly. The clones were equally sensitive to tert-butyl hydroperoxide, suggesting that the 7-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 7-OOH exposure, consistent with more rapid internalization and oxidative turnover in the former. [¹⁴C]7-OOH radioactivity accumulated much faster in SC2A mitochondria than in VC, whereas other subcellular fractions showed little rate difference. In keeping with this, 7-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.

Received for publication, January 25, 2006 , and in revised form, May 30, 2006.

^* This work was supported by United States Public Health Service, National Institutes of Health Grants CA72630 (to A. W. G.) and GM31651 (to F. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 414-456-8432; Fax: 414-456-6510; E-mail: agirotti{at}mcw.edu.

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