Mitochondrial cholesterol contributes to chemotherapy resistance in hepatocellular carcinoma.
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.
Montero
Joan
J
Liver Unit and Centro de Investigaciones Biomédicas Esther Koplowitz, IMDiM, Hospital Clínic i Provincial, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
Morales
Albert
A
Llacuna
Laura
L
Lluis
Josep M
JM
Terrones
Oihana
O
Basañez
Gorka
G
Antonsson
Bruno
B
Prieto
Jesús
J
García-Ruiz
Carmen
C
Colell
Anna
A
Fernández-Checa
José C
JC
D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000503:physiopathology; D002478:Cells, Cultured; D002784:Cholesterol / Q000032:analysis / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors; D020868:Gene Silencing; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D008930:Mitochondria, Liver / Q000737:chemistry*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics; D034741:RNA, Small Interfering / Q000627:therapeutic use; D051381:Rats; D023041:Xenograft Model Antitumor Assays; D000098682:Steroidogenic Acute Regulatory Protein
D000970:Antineoplastic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010750:Phosphoproteins; D034741:RNA, Small Interfering; D000098682:Steroidogenic Acute Regulatory Protein; D002784:Cholesterol; D013186:Farnesyl-Diphosphate Farnesyltransferase