Differential Regulation of Vitamin D Receptors in Clonal Populations of a Chronic Myelogenous Leukemia Cell Line

Iwata, Keigo; Kouttab, Nicola; Ogata, Haruki; Morgan, John; Maizel, Abby; Lasky, Stephen R.

doi:10.1006/excr.1996.0165

Cited by 7 publications

(3 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several laboratories, including ours, have developed 1,25D‐resistant sublines of human leukemic cells, but the mechanisms of the acquired resistance traits have not been clearly established. Suda's group proposed that 1,25D‐resistant variants of HL60 cells are due to mutations in VDR (Kuribayashi et al, 1983), while Lasky's group found that the VDR was not mutated in the 1,25D‐resistant variant of chronic myelogenous leukemia cell line, RWLeo‐4 (Lasky et al, 1994), and suggested that some process subsequent to VDR activation is altered in the resistant cells (Iwata et al, 1996). As indicated above, in cell types derived from solid tissues, resistance to 1,25D has been attributed to the susceptibility of the faster migrating VDR form to proteosomal degradation (Masuyama and MacDonald, 1998; Jensen et al, 2002), but the relevance to leukemia cells is not clear.…”

Section: Discussionmentioning

confidence: 99%

Resistance to 1,25D‐induced differentiation in human acute myeloid leukemia HL60‐40AF cells is associated with reduced transcriptional activity and nuclear localization of the vitamin D receptor

Garay¹,

Donnelly²,

Wang³

et al. 2007

Journal Cellular Physiology

View full text Add to dashboard Cite

The anti-neoplastic effects of 1,25-dihydroxyvitamin D 3 (1,25D) are well documented in numerous tumor cell systems and animal models of cancer. However, despite this pre-clinical success, the clinical use of 1,25D is currently impeded by the dose-limiting hypercalcemia, and the risk of development of resistance to 1,25D. In this study, we investigated the mechanism of resistance to 1,25D of HL60-40AF cells, a model of drug-resistant acute myeloid leukemia, derived from HL60 cells by cultivation in the presence of 1,25D. The data indicate that transcriptional activity of vitamin D receptor (VDR) in 40AF cells increases only briefly when the cells are treated with 1,25D, despite greater basal cellular levels of VDR protein in the resistant than in the 1,25D-sensitive cells. Analysis of the 40AF VDR mRNA sequence indicated alterations in the 5 0 untranslated region (UTR), but coding domain variations were not observed. When resistance to 1,25D-induced differentiation of 40AF cells was reversed by a combination of 1,25D with potentiators of differentiation (plant derived antioxidants and a p38MAPK inhibitor), an increase in the level of nuclear VDR, as well as an increase in CYP24 mRNA expression was observed. These data suggest that decreased ability of 1,25D to induce VDR nuclear localization and the consequent VDR target gene transcription may be an important reason for the resistance of 40AF cells to 1,25D. Further, our data show that VDR localization and phosphorylation can be increased by combining 1,25D with potentiators of differentiation. Analysis of the mechanisms that underlie the reduction and potentiation of 1,25D-mediated changes in VDR activity may lead to the identification of new cellular targets that enhance 1,25D-induced monocytic differentiation.

show abstract

Section: Discussionmentioning

confidence: 99%

Resistance to 1,25D‐induced differentiation in human acute myeloid leukemia HL60‐40AF cells is associated with reduced transcriptional activity and nuclear localization of the vitamin D receptor

Garay¹,

Donnelly²,

Wang³

et al. 2007

Journal Cellular Physiology

View full text Add to dashboard Cite

show abstract

“…1,25-(OH) 2 D 3 stimulated differentiation of the OB 17 preadipocyte cell line (4) and induced immature basal layer skin cells to differentiate into keratinocytes (5). Hematopoietic cell lines can be induced to differentiate along the macrophage/monocyte pathway (6)(7)(8). 1,25-(OH) 2 D 3 inhibits proliferation of cells in several models of cancer, including myeloid leukemia, melanoma, and carcinomas of the breast, prostate, colon, and head and neck (3).…”

mentioning

confidence: 99%

Expression Profiling in Squamous Carcinoma Cells Reveals Pleiotropic Effects of Vitamin D3 Analog EB1089 Signaling on Cell Proliferation, Differentiation, and Immune System Regulation

Lin¹,

Nagai

Sladek

et al. 2002

Molecular Endocrinology

143

View full text Add to dashboard Cite

The active form of vitamin D3, 1alpha,25-dihydroxyvitamin D3 [1,25-(OH)2D3] is key mediator of calcium homeostasis and is a component of the complex homeostatic system of the skin. 1,25-(OH)2D3 regulates cellular differentiation and proliferation and has broad potential as an anticancer agent. Oligonucleotide microarrays were used to assess profiles of target gene regulation at several points over a 48 h period by the low calcemic 1,25-(OH)2D3 analog EB1089 in human SCC25 head and neck squamous carcinoma cells. One hundred fifty-two targets were identified, composed of 89 up- and 63 down-regulated genes distributed in multiple profiles of regulation. Results are consistent with EB1089 driving SCC25 cells toward a less malignant phenotype, similar to that of basal keratinocytes. Targets identified control inter- and intra-cellular signaling, G protein-coupled receptor function, intracellular redox balance, cell adhesion, and extracellular matrix composition, cell cycle progression, steroid metabolism, and more than 20 genes modulating immune system function. The data indicate that EB1089 performs three key functions of a cancer chemoprevention agent; it is antiproliferative, it induces cellular differentiation, and has potential genoprotective effects. While no evidence was found for gene-specific differences in efficacy of 1,25-(OH)2D3 and EB1089, gene regulation by 1,25-(OH)2D3 was generally more transient. Treatment of cells with 1,25-(OH)2D3 and the cytochrome P450 inhibitor ketoconazole produced profiles of regulation essentially identical to those observed with EB1089 alone, indicating that the more sustained regulation by EB1089 was due to its resistance to inactivation by induced 24-hydroxylase activity. This suggests that differences in action of the two compounds arise more from their relative sensitivities to metabolism than from differing effects on VDR function.

show abstract

“…In this situation the designation "resistant" is based on the lack of growth inhibition, even though, as discussed earlier in "Differentiation," above, some of these cells are still capable of being induced to differentiate [245,252]. For myelogenous leukemia cells similar observations have been made [410]. In the resistant MCF-7 cells this defect is not located at a very common site in the growth-inhibitory pathway of the cell, because the growth could still be inhibited with the antiestrogen tamoxifen (409).…”

Section: Resistance and Vitamin D Metabolismmentioning

confidence: 91%

Vitamin D

et al. 2011

View full text Add to dashboard Cite

Differential Regulation of Vitamin D Receptors in Clonal Populations of a Chronic Myelogenous Leukemia Cell Line

Cited by 7 publications

References 0 publications

Resistance to 1,25D‐induced differentiation in human acute myeloid leukemia HL60‐40AF cells is associated with reduced transcriptional activity and nuclear localization of the vitamin D receptor

Resistance to 1,25D‐induced differentiation in human acute myeloid leukemia HL60‐40AF cells is associated with reduced transcriptional activity and nuclear localization of the vitamin D receptor

Expression Profiling in Squamous Carcinoma Cells Reveals Pleiotropic Effects of Vitamin D3 Analog EB1089 Signaling on Cell Proliferation, Differentiation, and Immune System Regulation

Vitamin D

Contact Info

Product

Resources

About