title: Pyruvate dehydrogenase kinase expression and metabolic changes following dichloroacetate exposure in anoxic human colorectal cancer cells.
abstract: Dichloroacetate (DCA) is a small molecule that inhibits pyruvate dehydrogenase kinase (PDK) to constrain the aerobic glycolytic pathway observed in many cancer cells and effectively kill them with limited cytotoxicity on normal cells. We previously showed that DCA induced a cytoprotective effect in different human colorectal cancer (CRC) cell lines under anoxic conditions. In this study, we investigated the molecular and metabolic changes that may be providing this cytoprotection. The expression profiles of PDK isoforms in SW480 and LS174T cells along with subsequent changes in pyruvate dehydrogenase (PDH) phosphorylation were assessed following DCA exposure. Changes in mitochondrial activity and subsequent glucose consumption and lactate production were then examined. We show evidence of differential regulation in PDH phosphorylation between different human CRC cells leading to differences in mitochondrial activity following DCA exposure. However, these effects did not lead to significant changes in cellular metabolism nor growth. In conclusion, DCA may only be beneficial in treating a subset of tumor types based on their molecular profiles of different PDK isoforms.
authors.affiliation: Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada N1G 2W1. Electronic address: nho@uoguelph.ca.
authors.forename: Nelson
authors.initials: N
authors.lastname: Ho
authors.affiliation: Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada N1G 2W1. Electronic address: bcoomber@uoguelph.ca.
authors.forename: Brenda L
authors.initials: BL
authors.lastname: Coomber
mesh_terms: D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D005434:Flow Cytometry; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D007658:Ketone Oxidoreductases / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger; D019344:Lactic Acid; D003999:Dichloroacetic Acid; D007658:Ketone Oxidoreductases; C053164:pyruvate dehydrogenase (NADP+); D017346:Protein Serine-Threonine Kinases; D005947:Glucose
keywords: Anoxia; Colorectal cancer; Dichloroacetate; Mitochondrial function; Pyruvate dehydrogenase kinase