Metabolic reprogramming by PCK1 promotes TCA cataplerosis, oxidative stress and apoptosis in liver cancer cells and suppresses hepatocellular carcinoma.
Metabolic reprogramming by PCK1 promotes TCA cataplerosis, oxidative stress and apoptosis in liver cancer cells and suppresses hepatocellular carcinoma.
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PCK1的代谢重编程促进肝癌细胞中的TCA猝死、氧化应激和细胞凋亡，并抑制肝细胞癌
DOI：
10.1038/s41388-017-0070-6
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发表时间：
2018-03
期刊：
影响因子：
8
通讯作者：
Xiong Y
中科院分区：
文献类型：
--
作者：
Liu MX;Jin L;Sun SJ;Liu P;Feng X;Cheng ZL;Liu WR;Guan KL;Shi YH;Yuan HX;Xiong Y
磷酸烯醇式丙酮酸羧激酶（PEPCK或PCK）是肝脏代谢途径中维持血糖水平的第一个限速步骤。哺乳动物细胞表达两种PCK基因，分别编码细胞质（PCPEK-C或PCK 1）和线粒体（PEPCK-M或PCK 2）亚型。在包括结肠、肺和皮肤在内的几种器官的癌症中发现了两种PCK基因表达的增加，并与合成代谢和细胞增殖的增加有关。在此，我们报道了PCK 1和PCK 2基因在原发性肝细胞癌（HCC）中表达下调，并且PCK低表达与HCC患者的不良预后相关。PCK 1或PCK 2在肝癌细胞系中的强制表达在葡萄糖剥夺条件下导致严重的凋亡，并抑制小鼠肝脏肿瘤的发生。从机制上讲，我们表明PCK 1的促凋亡作用需要其催化活性。我们证明，在葡萄糖饥饿的肝癌细胞中强制PCK 1表达诱导TCA cataplerosis，导致能量危机和氧化应激。补充TCA中间体α-酮戊二酸或抑制活性氧的产生可阻断PCK表达引起的细胞死亡。总之，我们的数据表明，PCK 1是有害的恶性肝细胞，并建议激活PCK 1的表达作为一个潜在的治疗策略，肝癌患者。
Phosphoenolpyruvate carboxykinase (PEPCK or PCK) catalyzes the first rate-limiting step in hepatic gluconeogenesis pathway to maintain blood glucose levels. Mammalian cells express twoPCKgenes, encoding for a cytoplasmic (PCPEK-C or PCK1) and a mitochondrial (PEPCK-M or PCK2) isoforms, respectively. Increased expressions of bothPCKgenes are found in cancer of several organs, including colon, lung, and skin, and linked to increased anabolic metabolism and cell proliferation. Here, we report that the expressions of bothPCK1andPCK2genes are downregulated in primary hepatocellular carcinoma (HCC) and low PCK expression was associated with poor prognosis in patients with HCC. Forced expression of either PCK1 or PCK2 in liver cancer cell lines results in severe apoptosis under the condition of glucose deprivation and suppressed liver tumorigenesis in mice. Mechanistically, we show that the pro-apoptotic effect of PCK1 requires its catalytic activity. We demonstrate that forced PCK1 expression in glucose-starved liver cancer cells induced TCA cataplerosis, leading to energy crisis and oxidative stress. Replenishing TCA intermediate α-ketoglutarate or inhibition of reactive oxygen species production blocked the cell death caused by PCK expression. Taken together, our data reveal that PCK1 is detrimental to malignant hepatocytes and suggest activating PCK1 expression as a potential treatment strategy for patients with HCC.
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DOI：
10.1042/bj20081386
发表时间：
2009-01-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Murphy MP
通讯作者：
Murphy MP
影响因子：
16
作者：
Montal ED;Dewi R;Bhalla K;Ou L;Hwang BJ;Ropell AE;Gordon C;Liu WJ;DeBerardinis RJ;Sudderth J;Twaddel W;Boros LG;Shroyer KR;Duraisamy S;Drapkin R;Powers RS;Rohde JM;Boxer MB;Wong KK;Girnun GD
通讯作者：
Girnun GD
影响因子：
25.7
作者：
Mendez-Lucas, Andres;Duarte, Joao Andre Goncalves;Sunny, Nishanth E.;Satapati, Santhosh;He, TianTeng;Fu, Xiaorong;Bermudez, Jordi;Burgess, Shawn C.;Perales, Jose C.
通讯作者：
Perales, Jose C.
影响因子：
2.9
作者：
Balan, Marc D.;Mcleod, Matthew J.;Holyoak, Todd
通讯作者：
Holyoak, Todd
影响因子：
16
作者：
Vincent, Emma E.;Sergushichev, Alexey;Jones, Russell G.
通讯作者：
Jones, Russell G.