Dichloroacetate affects proliferation but not survival of human colorectal cancer cells

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• 作者：L. M. Delaney ; N. Ho ; J. Morrison ; N. R. Farias ; D. D. Mosser ; B. L. Coomber
• 关键词：Mcl ; 1 ; Dichloroacetate ; Colorectal cancer ; p53 ; Bax
• 刊名：Apoptosis
• 出版年：2015
• 出版时间：January 2015
• 年：2015
• 卷：20
• 期：1
• 页码：63-74
• 全文大小：1,869 KB
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• 作者单位：L. M. Delaney (1)
  N. Ho (1)
  J. Morrison (1)
  N. R. Farias (1)
  D. D. Mosser (2)
  B. L. Coomber (1)
  
  1. Department of Biomedical Sciences, University of Guelph, Guelph, ON, N1G 2W1, Canada
  2. Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, N1G 2W1, Canada
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Oncology
  Cancer Research
  Cell Biology
  Biochemistry
  Virology
  
• 出版者：Springer Netherlands
• ISSN：1573-675X

文摘

Dichloroacetate (DCA) is a metabolic reprogramming agent that reverses the Warburg effect, causing cancer cells to couple glycolysis to oxidative phosphorylation. This has been shown to induce apoptosis and reduce the growth of various types of cancer but not normal cells. Colorectal cancer cells HCT116, HCT116 p53??/sup>, and HCT116 Bax??/sup>, were treated with DCA in vitro. Response to treatment was determined by measuring PDH phosphorylation, apoptosis, proliferation, and cell cycle. Molecular changes associated with these responses were determined using western immunoblotting and quantitative PCR. Treatment with 20?mM DCA did not increase apoptosis, despite decreasing levels of anti-apoptotic protein Mcl-1 after 6?h, in any of the cell lines observed. Mcl-1 expression was stabilized with MG-132, an inhibitor of proteasomal degradation. A decrease in Mcl-1 correlated with a decrease in proliferation, both of which showed dose-dependence in DCA treated cells. Cells showed nuclear localization of Mcl-1, however cell cycle was unaffected by DCA treatment. These data suggest that a reduction in the prosurvival Bcl-2 family member Mcl-1 due to increased proteasomal degradation is correlated with the ability of DCA to reduce proliferation of HCT116 human colorectal cancer cells without causing apoptosis.