1,25‐dihydroxyvitamin D<sub>3</sub> inhibits ultraviolet B‐induced apoptosis, Jun kinase activation, and interleukin‐6 production in primary human keratinocytes

Haes, Petra De; Garmyn, Marjan; Degreef, Hugo; Vantieghem, Katleen; Bouillon, Roger; Segaert, Siegfried

doi:10.1002/jcb.10540

Cited by 115 publications

(141 citation statements)

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“…Suppression of UV-stimulated IL-6 production by 1,25D was previously shown in keratinocytes (27) and we suspected that similar activity could be mediated by MKP5 in normal prostatic epithelial cells. Using MKP5 siRNA, we showed that 1,25D inhibited UV-stimulated p38 activity and IL-6 production in a MKP5-dependent manner in E-PZ cells.…”

Section: Discussionsupporting

confidence: 67%

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Inhibition of p38 by Vitamin D Reduces Interleukin-6 Production in Normal Prostate Cells via Mitogen-Activated Protein Kinase Phosphatase 5: Implications for Prostate Cancer Prevention by Vitamin D

et al. 2006

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Although numerous studies have implicated vitamin D in preventing prostate cancer, the underlying mechanism(s) remains unclear. Using normal human prostatic epithelial cells, we examined the role of mitogen-activated protein kinase phosphatase 5 (MKP5) in mediating cancer preventive activities of vitamin D. Up-regulation of MKP5 mRNA by 1,25-dihydroxyvitamin-D 3 (1,25D) was dependent on the vitamin D receptor. We also identified a putative positive vitamin D response element within the MKP5 promoter that associated with the vitamin D receptor following 1,25D treatment. MKP5 dephosphorylates/inactivates the stress-activated protein kinase p38. Treatment of prostate cells with 1,25D inhibited p38 phosphorylation, and MKP5 small interfering RNA blocked this effect. Activation of p38 and downstream production of interleukin 6 (IL-6) are proinflammatory. Inflammation and IL-6 overexpression have been implicated in the initiation and progression of prostate cancer. 1,25D pretreatment inhibited both UV-and tumor necrosis factor A-stimulated IL-6 production in normal cells via p38 inhibition. Consistent with inhibition of p38, 1,25D decreased UV-stimulated IL-6 mRNA stabilization. The ability of 1,25D to up-regulate MKP5 was maintained in primary prostatic adenocarcinoma cells but was absent in metastases-derived prostate cancer cell lines. The inability of 1,25D to regulate MKP5 in the metastasisderived cancer cells suggests there may be selective pressure to eliminate key tumor suppressor functions of vitamin D during cancer progression. These studies reveal MKP5 as a mediator of p38 inactivation and decreased IL-6 expression by 1,25D in primary prostatic cultures of normal and adenocarcinoma cells, implicating decreased prostatic inflammation as a potential mechanism for prostate cancer prevention by 1,25D. (Cancer Res 2006; 66(8): 4516-24)

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Section: Discussionsupporting

confidence: 67%

“…Published studies have shown that 1,25D inhibits UVinduced IL-6 production in keratinocytes; however, no mechanism has been proposed (27). IL-6 overexpression has been strongly associated with PCa progression and, therefore, inhibition of IL-6 may play an important role in PCa prevention.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of p38 by Vitamin D Reduces Interleukin-6 Production in Normal Prostate Cells via Mitogen-Activated Protein Kinase Phosphatase 5: Implications for Prostate Cancer Prevention by Vitamin D

et al. 2006

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“…Anti-apoptotic actions of 1,25-(OH) 2 D 3 have been described in keratinocytes (45,46), osteoblasts (47), lymphocytes (48), thyrocytes (49), and osteosarcoma cells (50). The functions are consistent with the positive physiological role of 1,25-(OH) 2 D 3 in regulating the survival and differentiation of cells of skin, bone, and the immune system.…”

Section: Discussionmentioning

confidence: 65%

Suppression of Death Receptor-mediated Apoptosis by 1,25-Dihydroxyvitamin D3 Revealed by Microarray Analysis

Zhang

Bao

et al. 2005

Journal of Biological Chemistry

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Vitamin D 3 (VD)2 is a steroid hormone best known for its role in calcium homeostasis. Its deficiency causes rickets in children and osteomalacia in adults. VD also regulates the proliferation and differentiation of normal and malignant cells of many tissue types. Because sunlight controls the first step of VD synthesis, namely, the photoconversion of 7-dehydrocholesterol to vitamin D 3 (1), the hormone is considered a "sun" medicine that is effective for the treatment and/or prevention of type II rickets, osteoporosis, autoimmune disorders, as well as epithelial cancers of many types.Ovarian cancer (OCa) is a fatal disease with an overall 5-year survival rate of about 40%. OCa mortality and incidence rates are lower in countries within 20 degrees of the equator (2) where there is a high amount of sunlight. In the United States, women between the ages of 45 and 54 living in the North have 5 times the OCa mortality rate of women living in Southern states (3). The inverse correlation between sunlight exposure and OCa mortality indicates that decreased synthesis of VD may contribute to OCa initiation and/or progression. This idea has been further substantiated by recent studies (4 -7) showing that 1,25-dihydroxyvitamin D 3 (1,25-(OH) 2 D 3 ), the active form of VD, inhibits the growth of multiple OCa cell lines (4 -6) and OVCAR3 tumor xenografts in nude mice (7).Effects of VD are mediated through the vitamin D receptor (8), which is a member of the steroid/thyroid receptor superfamily of ligand-regulated transcription factors. In response to the activation by 1,25-(OH) 2 D 3 , the receptor recruits multiple co-activators, including members of the p160 SRC family (9), which are associated with histone acetyltransferase activity, and the DRIP complex (10), which serves as a mediator between the vitamin D receptor and RNA polymerase II complex. Recent studies (11) have suggested that the anti-tumor activity of VD is mediated through its effect on gene transcription. In OCa cells, we have shown that the transcriptional up-regulation of GADD45 is essential for the 1,25-(OH) 2 D 3 -induced cell cycle arrest at the G 2 /M checkpoint (4). 1,25-(OH) 2 D 3 also increases p27 protein stability in OCa cells through down-regulation of Skp2 and cyclin E mRNA to induce cell cycle arrest at the G 1 /S checkpoint (6). These studies suggest that the action of 1,25-(OH) 2 D 3 through the nuclear activation of vitamin D receptor is important for the anti-tumor activity of the hormone in OCa.Because the anti-tumor activity of 1,25-(OH) 2 D 3 is mediated through regulation of gene expression, a more complete understanding of the mechanism underlying 1,25-(OH) 2 D 3 action in OCa cells necessitates identification of changes in gene expression induced by the hormone. In the present study, we profile transcriptional changes in OVCAR3 cells induced by 1,25-(OH) 2 D 3 using multiple independent microarray analyses. We concentrated our subsequent analysis to a few apoptosis-related genes from this list. Our studies reveal that 1,25-(OH) 2 D 3...

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“…1,25D3 inhibits UV B-induced apoptosis through the blockage of cytochrome c release from mitochondria in primary human keratinocytes (40). 1,25D3 upregulates Bcl-2 protein expression in normal human thyrocytes and protects them from apoptotic cell death (41).…”

Section: Discussionmentioning

confidence: 99%

Role of Nongenomic Activation of Phosphatidylinositol 3-Kinase/Akt and Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase/Extracellular Signal-Regulated Kinase 1/2 Pathways in 1,25D3-Mediated Apoptosis in Squamous Cell Carcinoma Cells

Kong

et al. 2006

Cancer Research

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1,25‐dihydroxyvitamin D₃ inhibits ultraviolet B‐induced apoptosis, Jun kinase activation, and interleukin‐6 production in primary human keratinocytes

Cited by 115 publications

References 49 publications

Inhibition of p38 by Vitamin D Reduces Interleukin-6 Production in Normal Prostate Cells via Mitogen-Activated Protein Kinase Phosphatase 5: Implications for Prostate Cancer Prevention by Vitamin D

Inhibition of p38 by Vitamin D Reduces Interleukin-6 Production in Normal Prostate Cells via Mitogen-Activated Protein Kinase Phosphatase 5: Implications for Prostate Cancer Prevention by Vitamin D

Suppression of Death Receptor-mediated Apoptosis by 1,25-Dihydroxyvitamin D3 Revealed by Microarray Analysis

Role of Nongenomic Activation of Phosphatidylinositol 3-Kinase/Akt and Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase/Extracellular Signal-Regulated Kinase 1/2 Pathways in 1,25D3-Mediated Apoptosis in Squamous Cell Carcinoma Cells

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1,25‐dihydroxyvitamin D3 inhibits ultraviolet B‐induced apoptosis, Jun kinase activation, and interleukin‐6 production in primary human keratinocytes

Cited by 115 publications

References 49 publications

Inhibition of p38 by Vitamin D Reduces Interleukin-6 Production in Normal Prostate Cells via Mitogen-Activated Protein Kinase Phosphatase 5: Implications for Prostate Cancer Prevention by Vitamin D

Inhibition of p38 by Vitamin D Reduces Interleukin-6 Production in Normal Prostate Cells via Mitogen-Activated Protein Kinase Phosphatase 5: Implications for Prostate Cancer Prevention by Vitamin D

Suppression of Death Receptor-mediated Apoptosis by 1,25-Dihydroxyvitamin D3 Revealed by Microarray Analysis

Role of Nongenomic Activation of Phosphatidylinositol 3-Kinase/Akt and Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase/Extracellular Signal-Regulated Kinase 1/2 Pathways in 1,25D3-Mediated Apoptosis in Squamous Cell Carcinoma Cells

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1,25‐dihydroxyvitamin D₃ inhibits ultraviolet B‐induced apoptosis, Jun kinase activation, and interleukin‐6 production in primary human keratinocytes