title: Activation of autophagy and PPARγ protect colon cancer cells against apoptosis induced by interactive effects of butyrate and DHA in a cell type-dependent manner: The role of cell differentiation.
abstract: The short-chain and n-3 polyunsaturated fatty acids exhibit anticancer properties, and they may mutually interact within the colon. However, the molecular mechanisms of their action in colon cancer cells are still not fully understood. Our study focused on the mechanisms responsible for the diverse effects of sodium butyrate (NaBt), in particular when interacting with docosahexaenoic acid (DHA), in distinct colon cancer cell types, in which NaBt either induces cell differentiation or activates programmed cell death involving mitochondrial pathway. NaBt activated autophagy both in HT-29 cells, which are sensitive to induction of differentiation, and in nondifferentiating HCT-116 cells. However, autophagy supported cell survival only in HT-29 cells. Combination of NaBt with DHA-promoted cell death, especially in HCT-116 cells and after longer time intervals. The inhibition of autophagy both attenuated differentiation and enhanced apoptosis in HT-29 cells treated with NaBt and DHA, but it had no effect in HCT-116 cells. NaBt, especially in combination with DHA, activated PPARγ in both cell types. PPARγ silencing decreased differentiation and increased apoptosis only in HT-29 cells, therefore we verified the role of caspases in apoptosis, differentiation and also PPARγ activity using a pan-caspase inhibitor. In summary, our data suggest that diverse responses of colon cancer cells to fatty acids may rely on their sensitivity to differentiation, which may in turn depend on distinct engagement of autophagy, caspases and PPARγ. These results contribute to understanding of mechanisms underlying differential effects of NaBt, when interacting with other dietary fatty acids, in colon cancer cells.
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, The Czech Academy of Sciences, Brno, Czech Republic; Department of Experimental Biology, Faculty of Sciences, Masaryk University, Brno, Czech Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Tylichová
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, The Czech Academy of Sciences, Brno, Czech Republic; International Clinic Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic. Electronic address: strakova@ibp.cz.
authors.forename: Nicol
authors.initials: N
authors.lastname: Straková
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, The Czech Academy of Sciences, Brno, Czech Republic; Department of Experimental Biology, Faculty of Sciences, Masaryk University, Brno, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Vondráček
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, The Czech Academy of Sciences, Brno, Czech Republic.
authors.forename: Alena Hyršlová
authors.initials: AH
authors.lastname: Vaculová
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, The Czech Academy of Sciences, Brno, Czech Republic; Department of Experimental Biology, Faculty of Sciences, Masaryk University, Brno, Czech Republic.
authors.forename: Alois
authors.initials: A
authors.lastname: Kozubík
authors.affiliation: Department of Cytokinetics, Institute of Biophysics, The Czech Academy of Sciences, Brno, Czech Republic; Department of Experimental Biology, Faculty of Sciences, Masaryk University, Brno, Czech Republic. Electronic address: hofmanova@ibp.cz.
authors.forename: Jiřina
authors.initials: J
authors.lastname: Hofmanová
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002087:Butyrates / Q000494:pharmacology*; D020148:Butyric Acid / Q000494:pharmacology; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology*; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D002087:Butyrates; D047495:PPAR gamma; D020148:Butyric Acid; D004281:Docosahexaenoic Acids; C505407:CASP3 protein, human; D053148:Caspase 3
keywords: Autophagy; Butyrate; Colon cancer; Differentiation; Docosahexaenoic acid; PPARγ