Calcitriol-mediated modulation of urokinase-type plasminogen activator and plasminogen activator inhibitor-2

Kole, Kerry; Gyetko, Margaret R.; Simpson, Robert U.; Sitrin, Robert G.

doi:10.1016/0006-2952(91)90631-e

Cited by 8 publications

(3 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The ability of vitamin D to modulate the plasminogen activator system in cancer cells has previously been reported for human U937 leukemia cells. However, in these cells, the expression of uPA is linked to induction of differentiation and is consequently up-regulated in response to treatment with vitamin D (187,188).…”

Section: Invasion and Metastasismentioning

confidence: 99%

Vitamin D and cancer: effects of 1,25(OH)2D3 and its analogs on growth control and tumorigenesis

Hansen

Binderup²,

Hamberg³

et al. 2001

Front Biosci

148

118

View full text Add to dashboard Cite

Today, it is well established that besides playing a crucial role in the establishment and maintenance of the calcium homeostasis in the body, the active form of vitamin D, 1,25(OH)2D3, also acts an effective regulator of cell growth and differentiation in a number of different cell types, including cancer cells. This has led to an increased interest in using 1,25(OH)2D3 in the treatment or prevention of cancer patients and to a substantial number of studies investigating the effect of 1,25(OH)2D3 on cancer cells. The results are encouraging, but clearly demonstrate that the therapeutic window of 1,25(OH)2D3 is extremely narrow due to the calcemic adverse effects of this compound. Much effort has consequently been directed into identifying vitamin D analogs with potent cell regulatory effects but with weaker effects on the calcium metabolism than those of 1,25(OH)2D3. In an attempt to clarify the mechanisms implicated in the cell regulatory effects of 1,25(OH)2D3 and eventually facilitate the process of developing new specific vitamin D analogs, numerous investigations have been carried out with 1,25(OH)2D3 and its analogs. The present review will focus on the results obtained in these studies and describe some of the synthetic analogs, which have shown to be of particular interest in relation to cancer.

show abstract

Section: Invasion and Metastasismentioning

confidence: 99%

Vitamin D and cancer: effects of 1,25(OH)2D3 and its analogs on growth control and tumorigenesis

Hansen

Binderup²,

Hamberg³

et al. 2001

Front Biosci

148

118

View full text Add to dashboard Cite

show abstract

“…The effects of VD3 on the uPA system have been reported in keratinocytes, osteoblasts, leukemic and breast tumor cells in culture [20,29,30,32]. Our approach to examine a possible regulation of the PA system by VD3 in fibroblasts and epithelial cells of the same tumor was to use organ culture, which preserves the interacting network of tumor cells, stromal fibroblasts, endothelial cells and extracellular matrix, representing, therefore, a good model for this evaluation.…”

Section: Introductionmentioning

confidence: 99%

“…The prognosis of breast and other cancers is ultimately determined by the tumor ability to invade and metastasize. Although the modulatory effects of VD3 or its analogous on the invasive process have been shown in a variety of human cancer cell types, relatively little is known regarding the molecular basis for the anti-invasive activity of VD3 in breast carcinomas [21,29,32,37,41,46].…”

Section: Introductionmentioning

confidence: 99%

Vitamin D3 modulation of plasminogen activator inhibitor type-1 in human breast carcinomas under organ culture

Barbosa

Nonogaki

Katayama³

et al. 2004

Virchows Archiv

View full text Add to dashboard Cite

Urokinase plasminogen activator (uPA), its cell-bound receptor (uPAR) and its main inhibitor plasminogen activator type 1 (PAI-1) are present primarily in stromal cells in invasive breast carcinoma. The purpose of this study was to investigate the regulation by 1,25 dihydroxyvitamin-D3 (VD3) of these invasion-associated markers expressed in breast cancer tumors under organ culture, which preserves the interacting network of tumor and stromal cells. Breast carcinoma slices (30 cases), obtained using the Krumdieck tissue slicer, cultured for 48 h in the presence or absence of 100 nM vitamin D3, were embedded in formalin-fixed paraffin. uPA, uPAR, PAI-1 and VD3 receptor (VDR) were analyzed by immunohistochemistry, and their expression, detected in tumor cells and fibroblasts of the specimens, was not statistically changed by culture conditions. The proportion of cases expressing uPA, uPAR and PAI-1 was not affected by VD3 in epithelial cells, but the fraction of cases displaying strong PAI-1 reactivity in fibroblasts was reduced ( P=0.016) compared with control slices. Fibroblasts isolated from invasive ductal carcinomas and from normal breast tissues expressed higher VDR mRNA levels than epithelial cells. In cultured tumor fibroblasts, PAI-1 immunostaining and mRNA levels were reduced by VD3-limiting fibroblast contribution to invasion.

show abstract

Urokinase expression in mononuclear phagocytes: cytokine-specific modulation by interferon-γ and tumor necrosis factor-α

Gyetko

Shollenberger

Sitrin

1992

Journal of Leukocyte Biology

View full text Add to dashboard Cite

This study delineates the regulatory effects of inflammatory cytokines on mononuclear phagocyte plasminogen activator (PA) activity. The mechanisms by which mononuclear phagocytes modulate PA activity are described. Mononuclear phagocytes regulate net PA activity by the balanced expression of urokinase-type PA (uPA), in either secreted or membrane-associated forms, and a specific plasminogen activator inhibitor, PAI-2. Therefore, understanding how immunomodulators regulate macrophage PA activity requires that the comparative effects of uPA and PAI-2 be elucidated. We determine how recombinant interferon-gamma (IFN) and tumor necrosis factor-alpha (TNF) regulate plasminogen activation in monoblast-like U937 cells and normal human monocytes. In U937 cells, both IFN and TNF induced concurrent increases in secreted PA and PA inhibitor activities. These effects were accompanied by increased immunoreactive uPA and PAI-2 in conditioned media (enzyme-linked immunosorbent assay) and steady-state levels of cellular uPA and PAI-2 mRNA (Northern analysis). To determine the relative abilities of IFN and TNF to either promote or inhibit plasmin generation, we directly compared the effects IFN and TNF, using optimal stimulating concentrations. IFN induced PA activity to 180% of the level achieved by TNF. In contrast, IFN elicited only 78% of the PA inhibitor produced by TNF stimulation. These differences in secreted activity can be explained by the shift in balance between uPA and PAI-2 proteins. Immunoreactive uPA was induced equally by IFN and TNF, but TNF generated higher levels of PAI-2. The same overall pattern of results was seen in normal human monocytes. IFN and TNF differ greatly in the ability to augment receptor-bound PA activity in U937 cells, as IFN induced a twofold increase but TNF had no effect. We conclude that IFN and TNF modulate mononuclear phagocyte proteolytic activity through coordinate regulation of secreted and receptor-bound uPA, balanced against concurrent expression of PAI-2. These effects are cytokine specific, as IFN is superior to TNF in stimulating expression of both secreted and receptor-associated PA activities. These properties suggest mechanisms by which mononuclear phagocytes control proteolysis in cytokine-rich inflammatory foci.

show abstract

Calcitriol-mediated modulation of urokinase-type plasminogen activator and plasminogen activator inhibitor-2

Cited by 8 publications

References 38 publications

Vitamin D and cancer: effects of 1,25(OH)2D3 and its analogs on growth control and tumorigenesis

Vitamin D and cancer: effects of 1,25(OH)2D3 and its analogs on growth control and tumorigenesis

Vitamin D3 modulation of plasminogen activator inhibitor type-1 in human breast carcinomas under organ culture

Urokinase expression in mononuclear phagocytes: cytokine-specific modulation by interferon-γ and tumor necrosis factor-α

Contact Info

Product

Resources

About