Loss of mitochondrial aconitase promotes colorectal cancer progression via SCD1-mediated lipid remodeling.
Loss of mitochondrial aconitase promotes colorectal cancer progression via SCD1-mediated lipid remodeling.
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线粒体乌头酸酶的缺失通过 SCD1 介导的脂质重塑促进结直肠癌进展
DOI：
10.1016/j.molmet.2021.101203
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发表时间：
2021-06
影响因子：
8.1
通讯作者：
Hu Y
中科院分区：
文献类型：
--
作者：
You X;Tian J;Zhang H;Guo Y;Yang J;Zhu C;Song M;Wang P;Liu Z;Cancilla J;Lu W;Glorieux C;Wen S;Du H;Huang P;Hu Y
线粒体顺乌头酸酶（ACO2）是一种重要的酶，在三羧酸循环和脂质代谢中起着桥梁作用。然而，其在癌症发展中的作用仍有待阐明。结直肠癌（CRC）的代谢亚型是最近建立的。我们研究了ACO2通过介导代谢改变在CRC进展中的潜在作用。我们比较了来自353例患者的配对CRC和非肿瘤组织中ACO2的mRNA和蛋白表达。研究了ACO2水平与临床病理特征之间的相关性。分析敲低或过表达AC0 2的CRC细胞系的细胞增殖和肿瘤生长。代谢组学和稳定同位素示踪分析被用来研究由ACO2的损失引起的代谢改变。与匹配的非肿瘤组织相比，在>50%的CRC样品中ACO2降低。ACO2水平的降低与疾病的晚期（P < 0.001）和患者生存期的缩短（P < 0.001）相关。敲低大肠癌细胞中的ACO2促进细胞增殖和肿瘤形成，而异位表达的ACO2抑制肿瘤生长。具体而言，阻断ACO2导致TCA循环中间体减少和线粒体氧化磷酸化抑制，导致糖酵解增加和脂肪酸和脂质合成的柠檬酸盐通量升高。柠檬酸盐流量增加诱导硬脂酰辅酶A去饱和酶（SCD 1）上调，这增强了ACO2缺乏细胞中的脂质去饱和，有利于结直肠癌生长。SCD的药理学抑制选择性地减少具有ACO2缺乏的CRC的肿瘤形成。我们的研究表明，重新布线的代谢途径维持CRC生存在受损的TCA周期和特点的治疗脆弱性脂质去饱和在一个有意义的子集CRC与线粒体功能障碍。在结直肠癌中经常观察到ACO2的丢失，并且与预后不良相关。ACO2的敲低促进结直肠癌进展。ACO2的敲低导致TCA循环紊乱并减弱氧化磷酸化。谷氨酰胺氧化在失去ACO2时维持柠檬酸盐生产的TCA循环。ACO2的抑制促进脂肪酸合成和脂质去饱和。
Mitochondrial aconitase (ACO2) is an essential enzyme that bridges the TCA cycle and lipid metabolism. However, its role in cancer development remains to be elucidated. The metabolic subtype of colorectal cancer (CRC) was recently established. We investigated ACO2's potential role in CRC progression through mediating metabolic alterations. We compared the mRNA and protein expression of ACO2 between paired CRC and non-tumor tissues from 353 patients. Correlations between ACO2 levels and clinicopathological features were examined. CRC cell lines with knockdown or overexpression of ACO2 were analyzed for cell proliferation and tumor growth. Metabolomics and stable isotope tracing analyses were used to study the metabolic alterations induced by loss of ACO2. ACO2 decreased in >50% of CRC samples compared with matched non-tumor tissues. Decreased ACO2 levels correlated with advanced disease stage (P < 0.001) and shorter patient survival (P < 0.001). Knockdown of ACO2 in CRC cells promoted cell proliferation and tumor formation, while ectopic expression of ACO2 restrained tumor growth. Specifically, blockade of ACO2 caused a reduction in TCA cycle intermediates and suppression of mitochondrial oxidative phosphorylation, resulting in an increase in glycolysis and elevated citrate flux for fatty acid and lipid synthesis. Increased citrate flux induced upregulation of stearoyl-CoA desaturase (SCD1), which enhanced lipid desaturation in ACO2-deficent cells to favor colorectal cancer growth. Pharmacological inhibition of SCD selectively reduced tumor formation of CRC with ACO2 deficiency. Our study demonstrated that the rewiring metabolic pathway maintains CRC survival during compromised TCA cycles and characterized the therapeutic vulnerability of lipid desaturation in a meaningful subset of CRC with mitochondrial dysfunction. Loss of ACO2 is frequently observed in colorectal cancer and is associated with poor prognosis. Knockdown of ACO2 promotes colorectal cancer progression. Knockdown of ACO2 leads to a perturbed TCA cycle and attenuates oxidative phosphorylation. Glutamine oxidation maintains the TCA cycle for citrate production upon loss of ACO2. Knockdown of ACO2 promotes fatty acid synthesis and lipid desaturation.
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DOI：
10.1158/1078-0432.ccr-12-3249
发表时间：
2013-05-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
von Roemeling CA;Marlow LA;Wei JJ;Cooper SJ;Caulfield TR;Wu K;Tan WW;Tun HW;Copland JA
通讯作者：
Copland JA
影响因子：
64.5
作者：
GRODEN, J;THLIVERIS, A;WHITE, R
通讯作者：
WHITE, R
影响因子：
37.3
作者：
Denkert C;Budczies J;Weichert W;Wohlgemuth G;Scholz M;Kind T;Niesporek S;Noske A;Buckendahl A;Dietel M;Fiehn O
通讯作者：
Fiehn O
影响因子：
3.7
作者：
Zarzour，Peter;Boelen，Lies;Wong，Jason W. H.
通讯作者：
Wong，Jason W. H.
影响因子：
4
作者：
Laiho, P;Hienonen, T;Aaltonen, LA
通讯作者：
Aaltonen, LA