Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress
Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress
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DOI：
10.1101/gad.1987211
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发表时间：
2011-05-15
影响因子：
10.5
通讯作者：
Mak, Tak W.
中科院分区：
文献类型：
--
作者：
Zaugg, Kathrin;Yao, Yi;Mak, Tak W.
肿瘤细胞通过调整其代谢来应对环境压力，这一过程被称为代谢转化，从而获得生存/生长优势。代谢转化最著名的方面是Warburg效应，即癌细胞在有氧条件下上调糖酵解。然而，介导代谢转化的其他机制仍未明确。在这里，我们报道了肉碱棕榈酰基转移酶1C (CPT1C)，一种脑特异性代谢酶，可能参与代谢转化。CPT1C表达与哺乳动物雷帕霉素靶蛋白（mTOR）通路激活呈负相关，有助于小鼠原发性肿瘤的雷帕霉素耐药，并且在人肺肿瘤中经常上调。组成性表达CPT1C的肿瘤细胞表现出脂肪酸（FA）氧化、ATP生成增加以及对葡萄糖剥夺或缺氧的抵抗。相反，缺乏CPT1C的癌细胞产生的ATP更少，对代谢应激更敏感。通过siRNA去除CPT1C抑制异种移植物肿瘤生长和体内二甲双胍反应。CPT1C可由缺氧或葡萄糖剥夺诱导，并受AMPK α调节。cpt1c缺陷小鼠胚胎干细胞（ES）对缺氧和葡萄糖剥夺敏感，并改变FA稳态。我们的研究结果表明，细胞可以利用一种涉及CPT1C和FA代谢的新机制来保护代谢应激。因此，CPT1C可能成为治疗缺氧肿瘤的新靶点。
Tumor cells gain a survival/growth advantage by adapting their metabolism to respond to environmental stress, a process known as metabolic transformation. The best-known aspect of metabolic transformation is the Warburg effect, whereby cancer cells up-regulate glycolysis under aerobic conditions. However, other mechanisms mediating metabolic transformation remain undefined. Here we report that carnitine palmitoyltransferase 1C (CPT1C), a brain-specific metabolic enzyme, may participate in metabolic transformation. CPT1C expression correlates inversely with mammalian target of rapamycin (mTOR) pathway activation, contributes to rapamycin resistance in murine primary tumors, and is frequently up-regulated in human lung tumors. Tumor cells constitutively expressing CPT1C show increased fatty acid (FA) oxidation, ATP production, and resistance to glucose deprivation or hypoxia. Conversely, cancer cells lacking CPT1C produce less ATP and are more sensitive to metabolic stress. CPT1C depletion via siRNA suppresses xenograft tumor growth and metformin responsiveness in vivo. CPT1C can be induced by hypoxia or glucose deprivation and is regulated by AMPK alpha. Cpt1c-deficient murine embryonic stem (ES) cells show sensitivity to hypoxia and glucose deprivation and altered FA homeostasis. Our results indicate that cells can use a novel mechanism involving CPT1C and FA metabolism to protect against metabolic stress. CPT1C may thus be a new therapeutic target for the treatment of hypoxic tumors.