Molecular pathways: Fumarate hydratase-deficient kidney cancer--targeting the Warburg effect in cancer.
Molecular pathways: Fumarate hydratase-deficient kidney cancer--targeting the Warburg effect in cancer.
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DOI：
10.1158/1078-0432.ccr-13-0304
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发表时间：
2013-07-01
期刊：
影响因子：
--
通讯作者：
Rouault TA
中科院分区：
文献类型：
--
作者：
Linehan WM;Rouault TA
遗传性平滑肌瘤病和肾细胞癌（HLRCC）是一种遗传性癌症综合征，其中受影响的个体有发生皮肤和子宫平滑肌瘤的风险，并且是II型乳头状肾癌的侵袭性形式。HLRCC的特征在于三羧酸循环（TCA）酶富马酸水合酶（FH）的种系突变。FH缺陷型肾癌的特征是氧化磷酸化受损和代谢向有氧糖酵解转变，这是一种称为瓦尔堡效应的代谢重编程形式。糖酵解的增加产生细胞增殖所需的ATP。在FH缺乏型肾癌中，AMPK（一种细胞能量传感器）的水平降低;导致p53水平降低，铁输入者DMT 1的表达降低，导致细胞铁水平降低，并通过减少乙酰辅酶A羧化酶的磷酸化（脂肪酸合成的限速步骤）来增强脂肪酸合成。FH缺陷型肾癌细胞中富马酸盐增加和铁水平降低可抑制脯氨酰羟化酶，从而稳定HIF 1 α，并增加血管内皮生长因子（VEGF）和GLUT 1等基因的表达，以提供快速生长所需的燃料。靶向FH缺陷型肾癌代谢基础的几种治疗方法正在开发中或正在临床试验中进行评估，包括使用二甲双胍等药物，其可逆转AMPK的失活，抑制葡萄糖转运、LDH-A、抗氧化反应途径的方法，血红素加氧酶途径和用诸如贝伐单抗和埃罗替尼的药剂靶向肿瘤脉管系统和葡萄糖转运的方法。这些相同类型的代谢转变，即有氧糖酵解和氧化磷酸化减少，在各种其他癌症类型中也有发现。针对罕见癌症（如富马酸水合酶缺乏型肾癌）的代谢基础，有望为开发其他更常见癌症的有效治疗形式提供见解。
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a hereditary cancer syndrome in which affected individuals are at risk for development of cutaneous and uterine leiomyomas and an aggressive form of type II papillary kidney cancer. HLRCC is characterized by germline mutation of the tricarboxylic acid cycle (TCA) enzyme, fumarate hydratase (FH). FH-deficient kidney cancer is characterized by impaired oxidative phosphorylation and a metabolic shift to aerobic glycolysis, a form of metabolic reprogramming referred to as the Warburg effect. Increased glycolysis generates ATP needed for increased cell proliferation. In FH-deficient kidney cancer levels of AMPK, a cellular energy sensor, are decreased; resulting in diminished p53 levels, decreased expression of the iron importer, DMT1, leading to low cellular iron levels, and to enhanced fatty acid synthesis by diminishing phosphorylation of acetyl CoA carboxylase, a rate limiting step for fatty acid synthesis. Increased fumarate and decreased iron levels in FH-deficient kidney cancer cells inactivate prolyl hydroxylases, leading to stabilization of HIF1α, and increased expression of genes such as vascular endothelial growth factor (VEGF) and GLUT1 to provide fuel needed for rapid growth demands. Several therapeutic approaches for targeting the metabolic basis of FH-deficient kidney cancer are under development or are being evaluated in clinical trials, including the use of agents such as metformin, which would reverse the inactivation of AMPK, approaches to inhibit glucose transport, LDH-A, the anti-oxidant response pathway, the heme oxygenase pathway and approaches to target the tumor vasculature and glucose transport with agents such as bevacizumab and erlotinib. These same types of metabolic shifts, to aerobic glycolysis with decreased oxidative phosphorylation, have been found in a wide variety of other cancer types. Targeting the metabolic basis of a rare cancer such as fumarate hydratase-deficient kidney cancer will hopefully provide insights into the development of effective forms of therapies for other, more common forms of cancer.