Antiproliferative effect of a vitamin D3 analog, EB1089, on HL-60 cells by the induction of TGF-beta receptor.
EB1089 is a novel 1,25(OH)2D3 analog that has more potent antitumor properties with reduced hypercalcemic effects than 1,25(OH)2D3. We investigated the role of transforming growth factor-beta1 (TGF-beta1) in the growth inhibition of human acute myeloid leukemia cell line, HL-60, by EB1089. Clonal growth of HL-60 cells was inhibited in a dose-dependent manner by EB1089. Although TGF-beta1 alone slightly inhibited proliferation of HL-60 cells, the addition of TGF-beta1 into culture treated with 10(-8) M of EB1089 showed a significant synergistic antiproliferative effect in a dose-dependent manner. EB1089 up-regulated the expression of TGF-beta receptor type I (TGF-beta RI), type II (TGF-beta RII) and TGF-beta1. Antiproliferative effect of EB1089 was partially reversed by TGF-beta1 neutralizing antibody (anti-TGF-beta1). Vitamin D receptor (VDR) expression was increased by TGF-beta1, suggesting synergistic action of TGF-beta1 and EB1089. Combined treatment of EB1089 and TGF-beta1 resulted in an increased expression of cyclin-dependent kinase inhibitor (CDKI), p27 protein, compared to either ligand alone. Up-regulation of p27 protein expression by either TGF-beta1 or EB1089 was reduced by anti-TGF-beta1. These findings suggest that TGF-beta1 is involved in the antiproliferative effect of EB1089 on HL-60 cells.
Jung
C W
CW
Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, South Korea.
Kim
E S
ES
Seol
J G
JG
Park
W H
WH
Lee
S J
SJ
Kim
B K
BK
Lee
Y Y
YY
D030201:Activin Receptors, Type I; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology; D018797:Cell Cycle Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006131:Growth Inhibitors / Q000494:pharmacology*; D018922:HL-60 Cells / Q000187:drug effects*; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018167:Receptors, Calcitriol / Q000096:biosynthesis / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D014410:Tumor Stem Cell Assay; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D006131:Growth Inhibitors; D018167:Receptors, Calcitriol; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D002117:Calcitriol; C078903:seocalcitol