Derivatives of vitamins D2 and D3 activate three MAPK pathways and upregulate pRb expression in differentiating HL60 cells.
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 D(3) (PRI-1890), 24-ene-1,25-dihydroxyvitamin D(2) (PRI-1906) and (24R)-1,24-dihydroxyvitamin D(3) (PRI-2191) to induce markers (CD14, CD11b and MSE) of differentiation, G(1) 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 G(1) checkpoint, by increasing the amount of substrate for cyclin-dependent kinases.
Ji
Yan
Y
Department of Pathology and Laboratory Medicine, UMDNJ, New Jersey Medical School, Newark, New Jersey, USA.
Kutner
Andrzej
A
Verstuyf
Annemieke
A
Verlinden
Lieve
L
Studzinski
George P
GP
D015415:Biomarkers; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism; D002762:Cholecalciferol / Q000494:pharmacology* / Q000627:therapeutic use; D018844:Cyclin-Dependent Kinases / Q000187:drug effects / Q000378:metabolism; D004872:Ergocalciferols / Q000494:pharmacology*; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000187:drug effects* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D015415:Biomarkers; D004872:Ergocalciferols; D016160:Retinoblastoma Protein; D002762:Cholecalciferol; D018844:Cyclin-Dependent Kinases