Inhibition by 1alpha,25-dihydroxyvitamin D3 of activin A-induced differentiation of murine erythroleukemic F5-5 cells.
1alpha,25-Dihydroxyvitamin D3 (1alpha,25-(OH)2D3) and other vitamin D3 (VD3) analogs enhanced the inhibitory effect of Activin A on murine erythroleukemia (MEL) cell proliferation and differentiation in a dose-dependent manner. 1alpha,25-(OH)2D3 inhibited differentiation more potently than proliferation by one order of magnitude. The VD3 analog study demonstrated either effect of VD3 on MEL cells via vitamin D receptor (VDR), as evidenced from the close relationship with the reported affinities for VDR. The effects of 1alpha,25-(OH)2D3 were preceded by the suppression of ornithine decarboxylase (ODC) activity, a rate-limiting enzyme in polyamine metabolism. Difluoromethylornithine (DFMO), an inhibitor of ODC, inhibited MEL cell proliferation, which was reversed by the simultaneous addition of putrescine, a product of ODC, but did not affect differentiation. 1alpha,25-(OH)2D3 inhibited cell differentiation during the phenotype-expression stage as reflected by the inhibition of beta-globin gene expression, while it inhibited proliferation in the commitment stage. Furthermore, it seems unlikely that the different effects of VD3 on proliferation and differentiation may be a result of upregulation of VDR or nongenomic action. In summary, it was suggested that 1alpha,25-(OH)2D3 inhibited Activin A-induced MEL cell proliferation and differentiation by distinct mechanisms and inhibited the proliferation by inhibiting ODC activity. We demonstrated the presence of 1alpha,25-(OH)2D3 action on leukemic cells at physiological concentration, which was distinct from the pharmacological effect of VD3 reported thus far.
Nagasaki
T
T
Second Department of Biochemistry, Osaka City University Medical School, Abeno-ku, Osaka, Japan.
Hino
M
M
Inaba
M
M
Nishizawa
Y
Y
Morii
H
H
Otani
S
S
D000123:Acetyltransferases / Q000378:metabolism; D028341:Activins; D000818:Animals; D002117:Calcitriol / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002762:Cholecalciferol / Q000031:analogs & derivatives / Q000494:pharmacology; D000518:Eflornithine / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005914:Globins / Q000096:biosynthesis; D006133:Growth Substances / Q000494:pharmacology; D007265:Inhibins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007700:Kinetics; D004915:Leukemia, Erythroblastic, Acute / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009955:Ornithine Decarboxylase / Q000378:metabolism*; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis; D018167:Receptors, Calcitriol / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D028341:Activins; D002117:Calcitriol; D002762:Cholecalciferol; D000518:Eflornithine; D005914:Globins; D006133:Growth Substances; D007265:Inhibins; D009955:Ornithine Decarboxylase; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D019009:Proto-Oncogene Proteins c-kit; D018167:Receptors, Calcitriol; D000099228:Diamine N-Acetyltransferase