Mitochondrial cholesterol contributes to chemotherapy resistance in hepatocellular carcinoma
Mitochondrial cholesterol contributes to chemotherapy resistance in hepatocellular carcinoma
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DOI：
10.1158/0008-5472.can-07-6161
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发表时间：
2008-07-01
期刊：
影响因子：
11.2
通讯作者：
Fernandez-Checa, Jose C.
中科院分区：
文献类型：
--
作者：
Montero, Joan;Morales, Albert;Fernandez-Checa, Jose C.
胆固醇代谢在癌变过程中被解除调控，癌细胞表现出线粒体胆固醇含量增加，其在细胞死亡易感性和癌症治疗中的作用尚未被研究。在这里，我们描述了来自大鼠或人类肝细胞癌(HC)细胞的线粒体或来自HC患者的原发肿瘤的线粒体胆固醇水平升高。当胆固醇耗尽时，通过抑制羟甲基戊二酰辅酶A还原酶或角鲨烯合成酶(SS)，增强了肝癌对通过线粒体作用的化疗的敏感性，角鲨烯合成酶催化了胆固醇生物合成的第一步。针对类固醇合成急性调节蛋白STAR的siRNA转染肝癌，使其对化疗增敏。STAR是一种线粒体胆固醇转运多肽，与大鼠和人肝相比在肝癌中过表达。从肝细胞癌分离的线粒体，随着胆固醇水平的升高，对线粒体膜通透性和细胞色素c或Smac/Diablo的释放具有抵抗作用，以响应包括活性Bax在内的各种刺激。在富含胆固醇的线粒体或脂质体中也观察到了类似的行为，并通过恢复线粒体膜秩序或提取胆固醇来逆转。此外，阿托伐他汀或SS抑制剂YM-53601在体内增强了阿霉素介导的肝癌生长停滞和细胞死亡。因此，线粒体胆固醇通过增加膜的有序性而导致化疗耐药，成为癌症治疗中的一种新的治疗利基。
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.