Inhibition by 1,25 dihydroxyvitamin D3 of chemically induced erythroid differentiation of K562 leukemia cells

The physiologically active form of vitamin D, 1,25 dihydroxyvitamin D₃ [1,25(OH)₂D₃], was found to inhibit erythroid differentiation of human leukemic K562 cells. Differentiation was induced by 1 μmol/L arabinocytosine (Ara-C), 40 μmol/L. tiazofurin, 1 μmol/L aphidicolin, or 1 μmol/L hydroxyurea, and was monitored daily by the appearance of hemoglobin in an increasing proportion of cells. Pretreatment for 48 hours with 2.4 × 10^-8 mol/L 1,25(OH)₂D₃, a concentration that is also optimal for induction of monocytic differentiation of HL-60 cells, reproducibly inhibited subsequent induction of erythroid differentiation by all of the above inducers, and modified the morphologic changes that Ara-C produced in these cells. The inhibition of hemoglobinization was approximately 50% irrespective of the degree of differentiation produced by the various inducers, but growth inhibition associated with exposure to the inducers was not affected by 1,25(OH)₂D₃. Similar inhibition of differentiation by 1,25(OH)₂D₃ was observed in mouse erythroleukemia cells MEL-D1B treated with 5 mmol/L hexamethylenebisacetamide. The inhibitory effect of 1,25(OH)₂D₃ on erythroid differentiation of K562 cells was abrogated by cyclohexamide (20 μg/mL), an inhibitor of protein synthesis. The mRNA for 1,25(OH)₂D₃ receptor (VDR) was detected in K562 cells, and was downregulated by a 96-hour exposure to 1,25(OH)₂D₃ or a 48-hour exposure to Ara-C. The presence of VDR mRNA suggests a physiologic role for 1,25(OH)₂D₃ in K562 cells that are precursors of erythroid cells. This role is perhaps to shift the pathways of differentiation from the erythroid to the monocytic lineage.