title: Dichloroacetate affects proliferation but not survival of human colorectal cancer cells.
abstract: 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(-/-), and HCT116 Bax(-/-), 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.
authors.affiliation: Department of Biomedical Sciences, University of Guelph, Guelph, ON, N1G 2W1, Canada.
authors.forename: L M
authors.initials: LM
authors.lastname: Delaney
authors.forename: N
authors.initials: N
authors.lastname: Ho
authors.forename: J
authors.initials: J
authors.lastname: Morrison
authors.forename: N R
authors.initials: NR
authors.lastname: Farias
authors.forename: D D
authors.initials: DD
authors.lastname: Mosser
authors.forename: B L
authors.initials: BL
authors.lastname: Coomber
mesh_terms: D000963:Antimetabolites / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D055786:Gene Knockout Techniques; D045325:HCT116 Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D051028:bcl-2-Associated X Protein / Q000235:genetics*
chemical_list: D000963:Antimetabolites; C494826:BAX protein, human; D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D003999:Dichloroacetic Acid; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde