Derivatives of Vitamins D2and D3Activate Three MAPK Pathways and Upregulate pRb Expression in Differentiating HL60 Cells

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Abstract
Analogs of vitamin D have been synthesized which have reduced calcemic activities yet increased anti-proliferative and differentiation-inducing properties, raising expectations that they will be useful for treatment of human neoplastic diseases. In the present study we compared the abilities of three such analogs, 24a, 24b-dihomo-1,25-dihydroxyvitamin D3 (PRI-1890), 24-ene-1,25-dihydroxyvitamin D2(PRI-1906) and (24R)-1,24-dihydroxy-vitamin D3 (PRI-2191) to induce markers (CD14, CD11b and MSE) of differentiation, G1 phase block, and associated molecular events in human promyeloblastic leukemia cells HL60. We found that the potencies of the analogs to induce differentiation paralleled their activation of Erk, JNK and p38 mitogen-activated protein kinase (MAPK) pathways, and the anti-proliferative activity closely correlated with the extent of hypophosphorylation of retinoblastoma protein (pRb). Interestingly, low concentrations of derivatives of vitamin D, which were insufficient to induce any detectable changes in the cell cycle traverse, markedly increased the levels of total pRb, which was highly phosphorylated. These results suggest that pRb may have an unsuspected role in monocytic differentiation, perhaps to increase the sensitivity of the G1 checkpoint, by increasing the amount of substrate for cyclin-dependent kinases.