Mitochondrial cholesterol contributes to chemotherapy resistance in hepatocellular carcinoma

et al.
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.
Grant support: Research Center for Liver and Pancreatic Diseases Grant P50 AA 11999 funded by the US National Institute on Alcohol Abuse and Alcoholism; Plan Nacional de I+D Grants SAF2005-03923, SAF2005-03943, SAF2006-06780, BFU2005-06095, and FIS06/0395; the Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas supported by the Instituto de Salud Carlos III; the Ramon y Cajal Research Program (Ministry of Education and Science; A. Colell and A. Morales); and a predoctoral fellowship from the Basque Government (O. Terrones).