Dichloroacetate induces apoptosis and cell-cycle arrest in colorectal cancer cells.
Dichloroacetate induces apoptosis and cell-cycle arrest in colorectal cancer cells.
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DOI：
10.1038/sj.bjc.6605701
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发表时间：
2010-06-08
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
癌细胞高度依赖糖酵解。我们的目的是确定代谢从糖酵解转向线粒体呼吸是否会比正常细胞更优先地降低结直肠癌细胞的生长，并检查潜在的机制。用丙酮酸脱氢酶激酶抑制剂二氯乙酸（DCA）处理具有代表性的结直肠癌和非癌细胞系。二氯乙酸（20 mM）对非癌细胞生长无抑制作用，但对癌细胞增殖有明显抑制作用（P=0.009），与细胞凋亡和G2期细胞周期阻滞有关。最大的凋亡效应在转移性LoVo细胞中是明显的，在48小时后，DCA诱导的凋亡细胞数量增加了10倍。在分化良好的HT29细胞中，最显著的G2阻滞是明显的，在48小时后，DCA使G2期细胞增加了8倍。二氯乙酸降低了生长培养基中的乳酸水平，并诱导了所有细胞系中丙酮酸脱氢酶复合物E1α亚基的去磷酸化，但线粒体固有膜电位仅在癌细胞中降低（P=0.04）。丙酮酸脱氢酶激酶抑制可减弱糖酵解并促进线粒体氧化磷酸化，导致结直肠癌细胞生长减少，而非癌细胞则不会。
Cancer cells are highly dependent on glycolysis. Our aim was to determine if switching metabolism from glycolysis towards mitochondrial respiration would reduce growth preferentially in colorectal cancer cells over normal cells, and to examine the underlying mechanisms. Representative colorectal cancer and non-cancerous cell lines were treated with dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase. Dichloroacetate (20 mM) did not reduce growth of non-cancerous cells but caused significant decrease in cancer cell proliferation (P=0.009), which was associated with apoptosis and G2 phase cell-cycle arrest. The largest apoptotic effect was evident in metastatic LoVo cells, in which DCA induced up to a ten-fold increase in apoptotic cell counts after 48 h. The most striking G2 arrest was evident in well-differentiated HT29 cells, in which DCA caused an eight-fold increase in cells in G2 phase after 48 h. Dichloroacetate reduced lactate levels in growth media and induced dephosphorylation of E1α subunit of pyruvate dehydrogenase complex in all cell lines, but the intrinsic mitochondrial membrane potential was reduced in only cancer cells (P=0.04). Pyruvate dehydrogenase kinase inhibition attenuates glycolysis and facilitates mitochondrial oxidative phosphorylation, leading to reduced growth of colorectal cancer cells but not of non-cancerous cells.
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影响因子：
8.8
作者：
Michelakis, E. D.;Webster, L.;Mackey, J. R.
通讯作者：
Mackey, J. R.
影响因子：
3.8
作者：
Sun, Ramon C.;Fadia, Mitali;Blackburn, Anneke C.
通讯作者：
Blackburn, Anneke C.
影响因子：
2.8
作者：
Cao, Wengang;Yacoub, Saif;Rosser, Charles J.
通讯作者：
Rosser, Charles J.
影响因子：
5.5
作者：
Wu, Min;Neilson, Andy;Ferrick, David A.
通讯作者：
Ferrick, David A.
影响因子：
7
作者：
Bi, Xuezhi;Lin, Qingsong;Hew, Choy-Leong
通讯作者：
Hew, Choy-Leong