Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is evidence that vitamin D receptor (VDR)-mediated action of 1 alpha,25-dihydroxyvitamin D3 (1 alpha,25-(OH)2D3) could limit colon cancer cell growth particularly when induced by activation of the epidermal growth factor receptor (EGFR). We therefore wanted to ascertain the relevance of this observation for human colon cancerogenesis. Utilizing in situ mRNA hybridization and immunocytochemical techniques, we analyzed cell-specific expression of VDR and EGFR in normal and malignant human colonic mucosa. In normal mucosa, VDR positivity is weak and observed only in a small number of luminal surface colonocytes. In contrast, EGFR expression at a relatively high level is also found in cells at the crypt base. The number of VDR-positive colonocytes increases remarkably during tumor progression. It reaches its maximum in low grade adenocarcinomas and returns to lower levels in highly malignant cancers. In both low- and high grade carcinomas, the great majority of tumor cells contain the EGFR message. The relative abundance of EGFR over VDR in normal mucosa and in high grade carcinomas would create a situation in which mitogenic effects from EGFR activation are only ineffectively counteracted by signaling from 1 alpha,25-(OH)2D3/VDR. In contrast, in well to moderately differentiated tumors, upregulation of VDR could retard further tumor progression.
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PMID:In situ mRNA hybridization analysis and immunolocalization of the vitamin D receptor in normal and carcinomatous human colonic mucosa: relation to epidermal growth factor receptor expression. 1114 70

1alpha,25(OH)2D3 is a potent growth inhibitor of different cancer cell lines. The steroid hormone is not only synthesized in the kidney, but also at extrarenal sites. Unfortunately, this potential autocrine/paracrine defense mechanism is lost during the late stages of colon tumor progression. It is therefore desirable to find a pharmacological means to maintain or enhance endogenous production of 1alpha,25(OH)2D3 during early periods in tumorigenesis. The phytoestrogen genistein was shown to regulate different cytochrome P450 enzymes, a family of proteins to which both of the vitamin D-metabolizing CYP27B1 (1alpha-hydroxylase) and CYP24 (24-hydroxylase) belong. Therefore, we used two colon cancer cell lines, Caco-2 and COGA-1, and investigated possible influences of genistein on different parameters of extrarenal vitamin D metabolism by HPLC, RT-PCR, and Western blot analysis. Differences between the two cell lines were found in both their basic enzymatic activities and in their response to treatment with 1alpha,25(OH)2D3. Whereas Caco-2 cells responded to administration of 100 nM genistein with a down-regulation of 24-hydroxylase activity, COGA-1 cells showed not only a significant down-regulation of 24-hydroxylase protein expression, but also a clear induction of vitamin D receptor (VDR) expression. Similar effects on VDR expression were achieved by administration of 10 nM 17beta-estradiol. This suggests an estrogenic mode of action of genistein, which might be dependent on differential distribution of estrogen receptors alpha and beta in our cell lines.
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PMID:Phytoestrogens and 17beta-estradiol influence vitamin D metabolism and receptor expression-relevance for colon cancer prevention. 1289 37

Though 1,25-dihydroxyvitamin D3 (1,25-D3) as well as some vitamin D analogs have an antimitotic as well as a differentiating action, therapeutic application in tumor patients is still precluded due to their hypercalcemic action at the necessary concentration. Our observation that early during progression, colon tumor cells express CYP27B1, the enzyme essential for 1,25-D3 synthesis, as well as the vitamin D receptor (VDR) at a higher level than normal colon cells led to the speculation that, by induction of this expression, a physiological defense against tumor progression could be activated and enhanced. In some Asian countries where soy products are a main staple, prostate and breast tumor incidence is extremely low. We speculated that this could be due to regulation of CYP enzymes by phytoestrogens present in soy such as genistein. In prostate tumor cells, the 1,25-dihydroxyvitamin D3 catabolizing enzyme CYP24 is frequently highly expressed. We were able to demonstrate that genistein down-regulates expression of CYP24 to almost nil, which would result in enhancement of local 1,25-D3 levels and improved mitotic control of tumor cells.
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PMID:Regulation of extrarenal vitamin D metabolism as a tool for colon and prostate cancer prevention. 1289 39

Epidemiological studies have demonstrated a high incidence of colonic tumors in populations living in areas of low sunlight exposure. This suggests 1,25-dihydroxyvitamin D3, an antimitotic prodifferentiating steroid hormone, as a potentially preventive factor since levels of the precursor 25-hydroxyvitamin D3 in serum are, to a major part, dependent upon sun exposure. Conversion into the active metabolite from the precursor is effected by CYP27B1, and degradation by CYP24. Both p450 hydroxylases are known to be located in the kidney. However, we were able to demonstrate presence, and activity of both enzymes also in the colon. We have shown also that during early tumor progression expression of CYP27B1 and of the vitamin D receptor is upregulated. Therefore the vitamin D system may function as a potent physiological defense against further tumor progression in cancer patients. We suggest that estrogenic substances, and also phytoestrogens present in soy food could, by increasing tumor tissue-located CYP27B1 activity and decreasing degradative CYP24 activity, augment tumor-localized 1,25-dihydroxyvitamin D3 levels and activity.
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PMID:Regulation of extrarenal synthesis of 1,25-dihydroxyvitamin D3--relevance for colonic cancer prevention and therapy. 1458 16

The active metabolite of vitamin D, 1alpha, 25-dihydroxyvitamin D3 [1,25(OH)2D3]--a seco-steroid hormone is a pivotal regulator of cellular proliferation and differentiation those are independent of its classical function of calcium homeostasis and bone mineralization. The existence of the nuclear vitamin D receptor (VDR) has been found in numerous tissues in different organs, which are the so-called 'non-classical' targets of this seco-steroid hormone. Vitamin D has been documented as a potent antiproliferative agent in different tissues and cells. Epidemiological studies reveal a negative correlation between physiological level of vitamin and cancer risk. Studies using animal models clearly demonstrate protective role of vitamin D in different cancer types by the reduction in tumor progression and by monitoring biochemical parameters. Experiments with cultured human and animal cancer cell lines show similar antiproliferative role of vitamin D manifested by up or down regulations of crucial genes leading to inhibition of cellular growth. Hypercalcemia hinders broad-spectrum therapeutic uses of vitamin D in cancer chemotherapy. Application of vitamin D analogs having similar chemical structures or other compounds having vitamin D like actions but lacking calcemic adverse effects are getting significant attention towards rational therapeutics to treat cancer. The current review focuses on the application of vitamin D and its analogs in different forms of cancer and on the molecular mechanism involved in vitamin D mediated inhibition in cellular proliferation, cell cycle, induction of apoptosis and tumor suppression, which may eventually evolve as a meaningful cancer therapy.
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PMID:Antiproliferative role of vitamin D and its analogs--a brief overview. 1461 76

Epidemiologic studies suggest that nutritional phytoestrogens contained in soy are causally related to protection against hormone-dependent cancers. The incidence of colorectal cancer is at least 30% lower in women than in men in the United States. This suggests that estrogen and, conceivably, nutritional phytoestrogens are protective compounds against colorectal cancer for both sexes. Prevention of colorectal, mammary, and prostate cancer may also depend on optimal synthesis of the antimitotic prodifferentiating vitamin D hormonal metabolite 1,25-(OH)(2)-cholecalciferol (1,25-D3). Cytochrome-P450-hydroxylases responsible for synthesis (CYP27B1; 25-D3-1 alpha-hydroxylase) and catabolism (CYP24; 1,25-D3-24-hydroxylase) of 1,25-D3 are not only present in the kidney but are also expressed in human colonocytes, prostate cells, and mammary cells. In addition, levels of CYP27B1, vitamin D receptor, and estrogen receptor-beta (the high-affinity receptor for phytoestrogens) are enhanced early during human colorectal cancer, which suggests an interactive physiological defense against tumor progression. We demonstrate in human mammary and prostate cells concentration-dependent regulation of CYP27B1 and of CYP24 by genistein at 0.05-50 micromol/L. The high concentration of 50 micromol/L is very effective in eliminating CYP24 expression in prostate cancer cells. This high concentration can be achieved in vivo in the prostate by an as-yet-unknown concentrative mechanism. Soy feeding, or more effectively genistein feeding, elevates CYP27B1 and reduces CYP24 expression in the mouse colon. In mice fed low nutritional calcium, CYP24 rises in parallel to enhanced colonic proliferation, and genistein counteracts both. We suggest that nutritional soy or genistein can optimize extrarenal 1,25-D3 synthesis, which could result in growth control and, conceivably, in inhibition of tumor progression.
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PMID:Phytoestrogens and vitamin D metabolism: a new concept for the prevention and therapy of colorectal, prostate, and mammary carcinomas. 1511 73

Several non-hypercalcemic analogs of 1alpha,25-dihydroxyvitamin D3 (1,25(OH)(2)D(3)) show antitumor activity in a subset of cancer patients. High vitamin D receptor (VDR) expression, which is associated with good prognosis but is lost during tumor progression. We show that the SNAIL transcription factor represses VDR gene expression in human colon cancer cells and blocks the antitumor action of EB1089, a 1,25(OH)(2)D(3) analog, in xenografted mice. In human colon cancers, elevated SNAIL expression correlates with downregulation of VDR.
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PMID:The transcription factor SNAIL represses vitamin D receptor expression and responsiveness in human colon cancer. 1532 38

The vitamin D receptor (VDR) is a member of the steroid/retinoid receptor superfamily of nuclear receptors that controls mineral ion homeostatis and has potential tumor-suppressive functions for various cancer types, specifically prostate cancer. A VDR ablated transgenic animal model (VDDRII, vitamin D-dependent rickets type II) has been developed and the animals typically have various diseases including, hypocalcemia, hyperparathyroidism, rickets, osteomalacia, and alopecia. This transgenic mouse system provides us with a model to decipher the influences of the VDR on prostatic growth and function. VDRs are abundant both in prostatic epithelial and stromal cells, and vitamin D signaling can be studied in this model. Although, there were no gross differences between the prostate tissue of the experimental and control groups, VDR null mice showed fat necrosis and individual cell apoptosis in the periprostatic adipose tissue. This indicates a possible role of VDR in the signaling pathways resulting the prostate. This may be particularly attractive for VDR targets for the inhibition of cancer progression using VD(3) and its analogs as potential chemo-preventive agents.
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PMID:Increased apoptosis of periprostatic adipose tissue in VDR null mice. 1535 70

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-D3 (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 alpha-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 metastasis-derived 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.
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PMID: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. 1661 80

ZEB1 and SNAIL repress CDH1 and induce epithelial-mesenchymal transition (EMT). However, SNAIL and ZEB1 also activate or regulate other target genes in different ways. For instance, vitamin D receptor (VDR), which activates CDH1 expression upon ligand binding, is repressed by SNAIL but induced by ZEB1. We examined whether the biological activity of SNAIL and ZEB1 in colon cancer is regulated by interacting cofactors. The mRNA expression levels of SNAIL and ZEB1, and of transcriptional regulators p300 and CtBP, were measured by RT-PCR in tumor and normal tissue from 101 colon carcinoma patients. Overexpression of SNAIL was associated with down-regulation of CDH1 and VDR (p = 0.004 and p < 0.001). CDH1 correlated with VDR (r = 0.49; p < 0.001). ZEB1 expression also correlated with VDR (r = 0.23; p = 0.019). However, when CtBP was strongly expressed, ZEB1 was inversely correlated with CDH1 (r = -0.39; p = 0.053). Furthermore, when there were elevated p300 expression levels, the correlation between expression of ZEB1 and VDR was stronger (r = 0.38; p = 0.070). Association between SNAIL expression and down-regulation of CDH1 and VDR was lost in tumors in which p300 and CtBP were strongly expressed. These results indicate that the levels of expression of CtBP and p300 are critical for the action of SNAIL and ZEB1, which have a pivotal role in EMT, and show the importance of CtBP and p300 for tumor progression.
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PMID:The expression levels of the transcriptional regulators p300 and CtBP modulate the correlations between SNAIL, ZEB1, E-cadherin and vitamin D receptor in human colon carcinomas. 1680 2


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