L-carnitine is an endogenous HDAC inhibitor selectively inhibiting cancer cell growth in vivo and in vitro.
L-carnitine is an endogenous HDAC inhibitor selectively inhibiting cancer cell growth in vivo and in vitro.
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L-肉碱是一种内源性 HDAC 抑制剂，可选择性抑制体内和体外癌细胞生长
DOI：
10.1371/journal.pone.0049062
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Liu J
中科院分区：
文献类型：
--
作者：
Huang H;Liu N;Guo H;Liao S;Li X;Yang C;Liu S;Song W;Liu C;Guan L;Li B;Xu L;Zhang C;Wang X;Dou QP;Liu J
一般认为，L-肉毒碱（LC）通过柠檬酸循环将脂肪酸中的长链酰基转运到线粒体基质中以产生ATP。根据瓦尔堡的理论，大多数癌细胞主要依赖糖酵解产生ATP，我们假设，LC治疗将导致细胞代谢紊乱和细胞毒性的癌细胞。本研究以人肝癌HepG 2、SMMC-7721细胞系、原代培养的胸腺细胞和荷瘤小鼠为研究对象。HPLC法测定ATP含量。流式细胞仪检测细胞周期，MTS检测细胞死亡率和细胞活力。分别采用基因芯片、Real-time PCR和Western blot检测基因、mRNA和蛋白水平。在试管和培养细胞中检测HDAC活性和组蛋白乙酰化。采用Discovery Studio 2.0中的CDOCKER程序进行分子对接，预测左旋肉碱与HDAC的分子相互作用。结果表明：（1）LC在体内外选择性抑制癌细胞生长，（2）LC选择性诱导癌细胞中p21 cip 1基因、mRNA和蛋白的表达，而不诱导p27 kip 1的表达，（4）LC促进正常胸腺细胞和癌细胞中组蛋白乙酰化，并诱导乙酰化组蛋白的积累;（5）LC通过与HDAC的活性位点结合直接抑制HDAC I/II活性，并诱导组蛋白乙酰化和赖氨酸乙酰化积累;（6）LC处理诱导与p21 cip 1基因相关的乙酰化组蛋白在染色质中积累，但ChIP检测未检测到p27 kip 1。这些数据支持LC除了转运酰基外，在细胞中还作为内源性HDAC抑制剂起作用，这将具有生理和病理重要性。
L-carnitine (LC) is generally believed to transport long-chain acyl groups from fatty acids into the mitochondrial matrix for ATP generation via the citric acid cycle. Based on Warburg's theory that most cancer cells mainly depend on glycolysis for ATP generation, we hypothesize that, LC treatment would lead to disturbance of cellular metabolism and cytotoxicity in cancer cells. In this study, Human hepatoma HepG2, SMMC-7721 cell lines, primary cultured thymocytes and mice bearing HepG2 tumor were used. ATP content was detected by HPLC assay. Cell cycle, cell death and cell viability were assayed by flow cytometry and MTS respectively. Gene, mRNA expression and protein level were detected by gene microarray, Real-time PCR and Western blot respectively. HDAC activities and histone acetylation were detected both in test tube and in cultured cells. A molecular docking study was carried out with CDOCKER protocol of Discovery Studio 2.0 to predict the molecular interaction between L-carnitine and HDAC. Here we found that (1) LC treatment selectively inhibited cancer cell growth in vivo and in vitro; (2) LC treatment selectively induces the expression of p21cip1 gene, mRNA and protein in cancer cells but not p27kip1; (4) LC increases histone acetylation and induces accumulation of acetylated histones both in normal thymocytes and cancer cells; (5) LC directly inhibits HDAC I/II activities via binding to the active sites of HDAC and induces histone acetylation and lysine-acetylation accumulation in vitro; (6) LC treatment induces accumulation of acetylated histones in chromatin associated with the p21cip1 gene but not p27kip1 detected by ChIP assay. These data support that LC, besides transporting acyl group, works as an endogenous HDAC inhibitor in the cell, which would be of physiological and pathological importance.
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影响因子：
56.9
作者：
Choudhary, Chunaram;Kumar, Chanchal;Mann, Matthias
通讯作者：
Mann, Matthias
影响因子：
8
作者：
Mateo, F.;Vidal-Laliena, M.;Canela, N.;Busino, L.;Martinez-Balbas, M. A.;Pagano, M.;Agell, N.;Bachs, O.
通讯作者：
Bachs, O.
影响因子：
64.8
作者：
Finnin, MS;Donigian, JR;Pavletich, NP
通讯作者：
Pavletich, NP
影响因子：
4.7
作者：
Chai, F;Evdokiou, A;Zalewski, PD
通讯作者：
Zalewski, PD
DOI：
10.1006/bbrc.2001.4434
发表时间：
2001-03-09
影响因子：
3.1
作者：
Kim, JS;Lee, SM;Trepel, JB
通讯作者：
Trepel, JB