1,25-Dihydroxycholecalciferol enhances butyrate-induced p21(Waf1/Cip1) expression.
Butyrate, a short-chain fatty acid produced in the colon, as well as its prodrug tributyrin, reduce proliferation and increase differentiation of colon cancer cells. p21(Waf1/Cip1) and p27(Kip1) are negative regulators of cell cycle and are thought to have a key function in the differentiation of various cell lines. We studied the effects of butyrate on differentiation, VDR expression, as well as on p21(Waf1/Cip1) and p27(Kip1) expression in human colon cancer cells (Caco-2). Butyrate induced cell differentiation, which was further enhanced after addition of 1,25-dihydroxycholecalciferol. Synergistic effect of butyrate and dihydroxycholecalciferol in Caco-2 cells was due to butyrate-induced overexpression of VDR. While butyrate as well as dihydroxycholecalciferol increased p21(Waf1/Cip1) and p27(Kip1) expression, in contrast combined exposure of butyrate and dihydroxycholecalciferol resulted in a synergistic amplification of p21(Waf1/Cip1), but not of p27(Kip1) expression. These data imply that butyrate selectively increases p21(Waf1/Cip1) expression via upregulation of VDR in Caco-2 cells.
Gaschott
T
T
Second Department of Medicine, Johann Wolfgang Goethe University, Frankfurt/Main, Germany.
Wächtershäuser
A
A
Steinhilber
D
D
Stein
J
J
D000469:Alkaline Phosphatase / Q000378:metabolism; D015153:Blotting, Western; D002087:Butyrates / Q000494:pharmacology*; D018938:Caco-2 Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002117:Calcitriol / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D015854:Up-Regulation / Q000187:drug effects
D002087:Butyrates; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D014280:Triglycerides; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000469:Alkaline Phosphatase; D002117:Calcitriol; C005830:tributyrin