Butyrate modulates DNA-damage-induced p53 response by induction of p53-independent differentiation and apoptosis.
Butyrate, a physiologically occurring agent, has been reported to decrease constitutively high expressed p53 levels in transformed cells. To elucidate whether butyrate also inhibits DNA-damage-induced p53 response we investigated the effects of butyrate and the anticancer drug mitomycin C in normal C3H10T1/2 cells harbouring wild-type p53. In comparison with p53-deficient fibroblasts we examined p53 protein level, cell cycle arrest, differentiation, and apoptosis. Butyrate induced G1 phase arrest, differentiation, and p53-independent increase in p21(waf1/cip1) protein. Moreover, butyrate induced p53-independent apoptosis, which was, as well as p53-mediated apoptosis, associated with a dose-dependent increase in Bax and c-Myc protein. Pretreatment with butyrate repressed dose-dependently mitomycin-C-induced p53 accumulation and interfered with p53-dependent cell cycle arrest. Butyrate further partially inhibited p53-mediated apoptosis, but low doses of butyrate were more effective than higher concentrations. This was reflected in an enhanced decrease in c-Myc and Bax protein in response to mitomycin C with low concentrations of butyrate. Our data indicate that the differentiation stimulus of butyrate, in association with p21(waf1/cip1) induction, and apoptosis, may explain antineoplastic effects of butyrate. Co-carcinogenic features of butyrate may result from inhibition of p53-mediated DNA damage response.
Janson
W
W
Department of Virology, Institute of Medical Microbiology and Hygiene, Albert-Ludwig-University, Freiburg, Germany.
Brandner
G
G
Siegel
J
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002087:Butyrates / Q000494:pharmacology*; D020148:Butyric Acid; D002453:Cell Cycle / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002461:Cell Line, Transformed; D004249:DNA Damage / Q000187:drug effects*; D053938:DNA Fragmentation; D019084:Fluorescent Antibody Technique, Indirect; D016158:Genes, p53; D051379:Mice; D016685:Mitomycin / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; D002087:Butyrates; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D020148:Butyric Acid; D016685:Mitomycin