Altered copper homeostasis underlies sensitivity of hepatocellular carcinoma to copper chelation.
Altered copper homeostasis underlies sensitivity of hepatocellular carcinoma to copper chelation.
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铜稳态的改变是肝细胞癌对铜螯合敏感性的基础。
DOI：
10.1039/d0mt00156b
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发表时间：
2020-12-23
期刊：
影响因子：
--
通讯作者：
Brady DC
中科院分区：
文献类型：
--
作者：
Davis CI;Gu X;Kiefer RM;Ralle M;Gade TP;Brady DC
肝细胞癌是最常见的原发性肝癌，今年全球将新增约80万例肝细胞癌，预示着不能切除的疾病患者的五年生存率仅为17%。这种令人沮丧的预后至少在一定程度上是由于诊断的后期和系统治疗的有限效果。因此，迫切需要确定导致肝细胞癌发生的危险因素，并提供有针对性的脆弱性以提高患者的存活率。虽然已知的危险因素有很多，但肝细胞癌患者铜水平的升高和肝豆状核变性患者肝胆恶性肿瘤的发生率显示出遗传性的肝脏铜超载，提示金属聚集促进恶性转化的可能性。在此，我们发现铜转运蛋白基因ATP7A、ATP7B、SLC31A1和SLC31A2在肝癌组织中的表达显著改变，并与肝癌组织和细胞中铜水平的升高有关。对基因组拷贝数数据的进一步分析表明，铜转运蛋白基因座的变化与肝细胞癌患者较差的生存相关。铜进口体SLC31A1(CTR1)的基因缺失或铜的药物抑制降低了人肝癌细胞系的存活率、克隆存活率和锚定非依赖性生长。从机制上讲，CTR1基因敲除或铜螯合降低了糖酵解基因的表达和下游代谢物的利用，从而阻止了肿瘤细胞在低氧暴露后存活，低氧模拟了经动脉栓塞术引起的缺氧，这是一种用于不能切除的肝癌患者的标准治疗方法。综上所述，这些发现建立了铜稳态改变与肝癌之间的联系，并表明限制铜的生物有效性可能通过限制癌细胞生存所需的代谢重新编程为肝癌提供一种新的治疗策略。在糖酵解成瘾的肝癌细胞中，生物可利用的铜为驱动肿瘤发生的致癌途径提供燃料。有趣的是，基因操作或对细胞内铜的药物抑制可以减少低氧诱导的糖酵解代谢，并减弱肝细胞癌的致癌特性。
Hepatocellular carcinoma (HCC), the most common primary liver cancer, of which ~800,000 new cases will be diagnosed worldwide this year, portends a five-year survival rate of merely 17% in patients with unresectable disease. This dismal prognosis is due, at least in part, from the late stage of diagnosis and the limited efficacy of systemic therapies. As a result, there is an urgent need to identify risk factors that contribute to HCC initiation and provide targetable vulnerabilities to improve patient survival. While myriad risk factors are known, elevated copper (Cu) levels in HCC patients and the incidence of hepatobiliary malignancies in Wilson disease patients, which exhibit hereditary liver Cu overload, suggests the possibility that metal accumulation promotes malignant transformation. Here we found that expression of the Cu transporter genes ATP7A, ATP7B, SLC31A1, and SLC31A2 were significantly altered in liver cancer samples and were associated with elevated Cu levels in liver cancer tissue and cells. Further analysis of genomic copy number data revealed that alterations in Cu transporter gene loci correlates with poorer survival in HCC patients. Genetic loss of the Cu importer SLC31A1 (CTR1) or pharmacologic suppression of Cu decreased the viability, clonogenic survival, and anchorage-independent growth of human HCC cell lines. Mechanistically, CTR1 knockdown or Cu chelation decreased glycolytic gene expression and downstream metabolite utilization and as a result forestall tumor cell survival after exposure to hypoxia, which mimics oxygen deprivation elicited by transarterial embolization, a standard-of-care therapy used for patients with unresectable HCC. Taken together, these findings established an association between altered Cu homeostasis and HCC and suggest that limiting Cu bioavailability may provide a new treatment strategy for HCC by restricting the metabolic reprogramming necessary for cancer cell survival. In glycolytic-addicted HCC cells, bioavailable Cu fuels oncogenic pathways that drive tumorigenesis. Intriguingly, genetic manipulation or pharmacologic inhibition of intracellular Cudiminishes hypoxia-induced glycolytic metabolism and attenuates HCC tumorigenic properties.
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影响因子：
30.8
作者：
BULL, PC;THOMAS, GR;COX, DW
通讯作者：
COX, DW
影响因子：
9.8
作者：
Altekruse, Sean F.;Henley, S. Jane;Cucinelli, James E.;McGlynn, Katherine A.
通讯作者：
McGlynn, Katherine A.
DOI：
10.1111/nyas.12337
发表时间：
2014-01-01
期刊：
HUMAN DISORDERS OF COPPER METABOLISM II
影响因子：
--
作者：
Huster, Dominik
通讯作者：
Huster, Dominik
影响因子：
3.6
作者：
Feng, Wenke;Ye, Fei;Kang, Y. James
通讯作者：
Kang, Y. James
影响因子：
11.2
作者：
Brady DC;Crowe MS;Greenberg DN;Counter CM
通讯作者：
Counter CM