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• W2004103680 abstract "Induction of growth arrest and monocyte differentiation of HL-60 leukemia cells by 1α,25 dihydroxyvitamin D3 (1α,25(OH)2D3) is well established. By contrast, we have observed, that 1α,25(OH)2D3 and its metabolites play separate roles in clonal expansion and survival of differentiating HL-60 cells. Cells that had differentiated by 48 h (CD14 positive) grew slower than control cells, whereas CD14 negative cells were growing faster at this time point. Inhibiting 1α,25(OH)2D3 or 1α,25(OH)2-20-epi-D3 metabolism, by the 25(OH)D3-24-hydroxylase inhibitor ketoconazole, abolished hyperproliferation of CD14 negative cells. Instead, both the onset of differentiation and subsequent apoptosis were enhanced. These events were associated with immediate up-regulation of the cyclin-dependent kinase inhibitor p21(waf1) and a lack of sustained expression, respectively. Stimulation and inhibition of growth by vitamin D3-related compounds was observed to be concentration and metabolite specific. Low amounts of 1α,25(OH)2-20-epi-D3 and 1α,24,25(OH)3-20-epi-D3 stimulated HL-60 cell growth. At higher concentrations, 1α,25(OH)2-20-epi-D3 was a more potent inducer than 1α,24,25(OH)3-20-epi-D3 of HL-60 differentiation; 1α,25(OH)2-20-epi-24-oxo-D3 was exclusively pro-differentiative at all concentrations. 1α,25(OH)2-20-epi-D3 and 1α,24,25(OH)3-20-epi-D3 stimulated proliferation of KG-1a leukemia cells, but neither of these compounds nor 1α,25(OH)3-20-epi-24-oxo-D3 exerted pro-differentiative effects on these cells. These findings shed new light on the pro- and anti-proliferative effects of 1α,25(OH)2D3 and lead to the postulate that metabolism of 1α,25(OH)2D3 and its 20-epi analog regulates different subsets of genes so as to co-ordinate population expansion and the differentiation process. Furthermore, 1α,25(OH)2D3 metabolism and/or sensitivity to the effects of metabolites may be altered in transformed cells to derive a clonal advantage." @default.
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• W2004103680 date "1999-03-01" @default.
• W2004103680 modified "2023-10-14" @default.
• W2004103680 title "Metabolism of 1α,25(OH)2D3 and its 20-epi analog integrates clonal expansion, maturation and apoptosis during HL-60 cell differentiation" @default.
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• W2004103680 doi "https://doi.org/10.1016/s0303-7207(98)00245-7" @default.
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