title: Ursodeoxycholic acid protects colon cancer HCT116 cells from deoxycholic acid-induced apoptosis by inhibiting apoptosome formation.
abstract: We previously demonstrated that ursodeoxycholic acid (UDC) requires prolonged (≥5 h) preincubation to exhibit effective protection of colon cancer HCT116 cells from deoxycholic acid (DC)-induced apoptosis. Although UDC diminished DC-mediated caspase-9 activation, cytochrome c release from the mitochondria was not inhibited, indicating that UDC acts on the steps of caspase-9 activation. In the present study, therefore, we investigated the effects of UDC on the factors involved in caspase-9 activation. We found that UDC had no significant effect on the expression of antiapoptotic XIAP. Furthermore, UDC did not affect the expression or release of proapoptotic Smac/DIABLO, or the association of XIAP and Smac/DIABLO. In contrast, association of Apaf-1 and caspase-9 stimulated by 500 μM DC was inhibited by UDC pretreatment. Although UDC caused remarkable activation of Akt/PKB, phosphatidylinositol-3-kinase (PI3K) inhibitor did not significantly reduce UDC-mediated cytoprotection. Furthermore, phosphorylation of threonine residues on caspase-9 after UDC pretreatment could not be detected. UDC-mediated cytoprotection was independent of the MAPK pathway, and cyclic AMP (cAMP) analogue did not inhibit DC-induced apoptosis. Our results indicate that UDC protects colon cancer cells from apoptosis induced by hydrophobic bile acids, by inhibiting apoptosome formation independently of the survival signals mediated by the PI3K, MAPK, or cAMP pathways.
authors.affiliation: Laboratory of Molecular Nutrition, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Sakyo-ku, Kyoto, Japan. tsaeki@kpu.ac.jp
authors.forename: Tohru
authors.initials: T
authors.lastname: Saeki
authors.forename: Satoko
authors.initials: S
authors.lastname: Yui
authors.forename: Tadashi
authors.initials: T
authors.lastname: Hirai
authors.forename: Takami
authors.initials: T
authors.lastname: Fujii
authors.forename: Sawami
authors.initials: S
authors.lastname: Okada
authors.forename: Ryuhei
authors.initials: R
authors.lastname: Kanamoto
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D053478:Apoptosomes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053477:Apoptotic Protease-Activating Factor 1 / Q000235:genetics / Q000378:metabolism; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism; D061945:Caspase Inhibitors; D003110:Colonic Neoplasms / Q000473:pathology; D003840:Deoxycholic Acid / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C506592:APAF1 protein, human; D053478:Apoptosomes; D053477:Apoptotic Protease-Activating Factor 1; D061945:Caspase Inhibitors; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D003840:Deoxycholic Acid; D014580:Ursodeoxycholic Acid; D051057:Proto-Oncogene Proteins c-akt; C506433:CASP9 protein, human; D053453:Caspase 9