Signaling of monocytic differentiation by a non-hypercalcemic analog of vitamin D3, 1,25(OH)2-5,6 trans-16-ene-vitamin D3, involves nuclear vitamin D receptor (nVDR) and non-nVDR-mediated pathways.
Exposure of leukemia cells to the physiologically active form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25D3) normalizes their phenotype to cells that resemble mature monocytes. One of the earliest detectable events in this process is an upregulation of the nuclear receptor for 1,25D3, the vitamin D receptor (nVDR). In contrast, the novel analog of 1,25D3, 1,25-dihydroxy-5,6 trans-16-ene-vitamin D3 (5,6-16D3), which has recently been reported to have low calcium-mobilizing activity in vivo, rapidly induced the expression of CD14, CD11b, and monocyte-specific esterase (MSE), classical markers of the mature monocyte, but upregulated nVDR expression less than 1,25D3. This upregulation was shown to be the result of altered degradation of the nVDR protein, while the levels of nVDR mRNA were constant. Knock-out of nVDR transcriptional activity by a decoy VDRE double-stranded deoxyoligonucleotide, markedly abrogated 1,25D3-induced differentiation, but incompletely inhibited 5,6-16D3-induced differentiation. These findings suggest that the unique ability of 5,6-16D3 to induce cell differentiation but not systemic hypercalcemia, may be due to the activation of pathways which initiate differentiation independently of nVDR.
Ji
Yan
Y
Department of Pathology and Laboratory Medicine, UMD-New Jersey Medical School, Newark 07103, USA.
Wang
Xuening
X
Donnelly
Robert J
RJ
Uskokovic
Milan R
MR
Studzinski
George P
GP
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002117:Calcitriol / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009841:Oligonucleotides / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D018167:Receptors, Calcitriol / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
C458880:1,25-dihydroxy-5,6-16-ene-vitamin D3; D000970:Antineoplastic Agents; D009841:Oligonucleotides; D018167:Receptors, Calcitriol; D002117:Calcitriol