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Mitochondrial Cholesterol Contributes to Chemotherapy Resistance in Hepatocellular Carcinoma

¹ Liver Unit and Centro de Investigaciones Biomédicas Esther Koplowitz, IMDiM, Hospital Clínic i Provincial, Institut d'Investigacions Biomèdiques August Pi i Sunyer, and Department of Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona, Spain; ² Centro de Investigación Biomédica en Red (CIBERehd); ³ Unidad de Biofísica (Centro Mixto Consejo Superior de Investigaciones Científicas-Universidad del País Vasco/Euskal Herriko Unibertsitatea), Universidad del País Vasco/Euskal Herriko Unibertsitatea, Bilbao, Spain; ⁴ Merck Serono Internacional, Geneva, Switzerland; and ⁵ Liver Unit and Division of Hepatology and Gene Therapy, University Clinic and Center for Applied Medical Research, University of Navarra, Pamplona, Spain

Requests for reprints: José C. Fernández-Checa, Liver Unit, Hospital Clínic i Provincial, C/Villarroel, 170, 08036-Barcelona, Spain. Phone: 34-93-227-5709; Fax: 34-93-451-5272; E-mail: checa229{at}yahoo.com.

Key Words: statins • squalene synthase inhibitor • mitochondrial membrane permeabilization • StAR • tumor xenografts

Cholesterol metabolism is deregulated in carcinogenesis, and cancer cells exhibit enhanced mitochondrial cholesterol content whose role in cell death susceptibility and cancer therapy has not been investigated. Here, we describe that mitochondria from rat or human hepatocellular carcinoma (HC) cells (HCC) or primary tumors from patients with HC exhibit increased mitochondrial cholesterol levels. HCC sensitivity to chemotherapy acting via mitochondria is enhanced upon cholesterol depletion by inhibition of hydroxymethylglutaryl-CoA reductase or squalene synthase (SS), which catalyzes the first committed step in cholesterol biosynthesis. HCC transfection with siRNA targeting the steroidogenic acute regulatory protein StAR, a mitochondrial cholesterol–transporting polypeptide which is overexpressed in HCC compared with rat and human liver, sensitized HCC to chemotherapy. Isolated mitochondria from HCC with increased cholesterol levels were resistant to mitochondrial membrane permeabilization and release of cytochrome c or Smac/DIABLO in response to various stimuli including active Bax. Similar behavior was observed in cholesterol-enriched mitochondria or liposomes and reversed by restoring mitochondrial membrane order or cholesterol extraction. Moreover, atorvastatin or the SS inhibitor YM-53601 potentiated doxorubicin-mediated HCC growth arrest and cell death in vivo. Thus, mitochondrial cholesterol contributes to chemotherapy resistance by increasing membrane order, emerging as a novel therapeutic niche in cancer therapy. [Cancer Res 2008;68(13):5246–56]

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