title: Butyrate-induced apoptosis in HCT116 colorectal cancer cells includes induction of a cell stress response.
abstract: Short chain fatty acids (SCFA), principally butyrate, propionate, and acetate, are produced in the gut through the fermentation of dietary fiber by the colonic microbiotica. Butyrate in particular is the preferred energy source for the cells in the colonic mucosa and has been demonstrated to induce apoptosis in colorectal cancer cell lines. We have used proteomics, specifically 2D-DIGE and mass spectrometry, to identify proteins involved in butyrate-induced apoptosis in HCT116 cells and also to identify proteins involved in the development of butyrate insensitivity in its derivative, the HCT116-BR cells. The HCT116-BR cell line was characterized as being less responsive to the apoptotic effects of butyrate in comparison to its parent cell line. Our analysis has revealed that butyrate likely induces a cellular stress response in HCT116 cells characterized by p38 MAPK activation and an endoplasmic reticulum (ER) stress response, resulting in caspase 3/7 activation and cell death. Adaptive cellular responses to stress-induced apoptosis in HCT116-BR cells may be responsible for the development of resistance to apoptosis in this cell line. We also report for the first time additional cellular processes altered by butyrate, such as heme biosynthesis and dysregulated expression of nuclear lamina proteins, which may be involved in the apoptotic response observed in these cell lines.
authors.affiliation: CSIRO Preventative Health Flagship, Australia. kim.fung@csiro.au
authors.forename: Kim Y C
authors.initials: KY
authors.lastname: Fung
authors.forename: Gemma V
authors.initials: GV
authors.lastname: Brierley
authors.forename: Steve
authors.initials: S
authors.lastname: Henderson
authors.forename: Peter
authors.initials: P
authors.lastname: Hoffmann
authors.forename: Shaun R
authors.initials: SR
authors.lastname: McColl
authors.forename: Trevor
authors.initials: T
authors.lastname: Lockett
authors.forename: Richard
authors.initials: R
authors.lastname: Head
authors.forename: Leah
authors.initials: L
authors.lastname: Cosgrove
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002087:Butyrates / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism*; D004789:Enzyme Activation; D005232:Fatty Acids, Volatile / Q000737:chemistry; D045325:HCT116 Cells / Q000187:drug effects* / Q000502:physiology*; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D006360:Heat-Shock Proteins; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D013058:Mass Spectrometry / Q000379:methods; D018832:Molecular Chaperones; D040901:Proteomics / Q000379:methods; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D013312:Stress, Physiological; D057825:Two-Dimensional Difference Gel Electrophoresis / Q000379:methods
chemical_list: D002087:Butyrates; D005232:Fatty Acids, Volatile; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D011518:Proto-Oncogene Proteins; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human; D053148:Caspase 3; D053179:Caspase 7