Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0007112 (prostatic adenocarcinoma)
 2,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parathyroid hormone-related protein (PTHrP) has previously been shown to be expressed in human prostatic tissue and in prostatic cancer cell lines. In the present study, PTHrP immunoreactivity was detected in the glandular epithelium of normal prostate and benign prostatic hyperplasia (BPH), as well as in prostatic adenocarcinoma (CaP). Epithelial cell cultures derived from normal, BPH, and CaP tissues were also stained by antibodies against PTHrP, and northern analysis revealed multiple transcripts of PTHrP in the cellular RNA. PTHrP (1-34) was measurable by radioimmunoassay (RIA) in media conditioned by the prostatic epithelial cell cultures, and PTHrP accumulated in conditioned media during a 72 hr time course. Addition of complete growth medium to starved cells resulted in increased PTHrP mRNA levels by 1 hr, with maximal stimulation at 8-24 hr. Several individual factors contained in the complete growth medium were tested for their ability to regulate PTHrP expression. Epidermal growth factor (EGF) was the major inducer of PTHrP expression, while cholera toxin, bovine pituitary extract, hydrocortisone, and insulin had minimal or no effect on PTHrP transcript levels. Since each of these factors is growth stimulatory, the unique ability of EGF to induce PTHrP is apparently unrelated to mitogenicity. 1,25-Dihydroxyvitamin D3[1,25(OH)2D3], an inhibitor of PTHrP expression in several other cell types, had no effect on steady-state levels of PTHrP mRNA expressed by epithelial cells in complete growth medium, although prostate cells have vitamin D receptors and are responsive to 1,25(OH)2D3 in other ways. Our results indicate that PTHrP expression is not confined to the neuroendocrine cells of the human prostate and that our culture system can be used as a model to investigate the role of PTHrP in the prostate.
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PMID:Parathyroid hormone--related protein (PTHrP) is an epidermal growth factor-regulated secretory product of human prostatic epithelial cells. 868 51

Recent studies have proposed that exposure to ultraviolet radiation (UVR) protects against development of some internal cancers including that in prostate. This effect may be mediated by UVR-induced cutaneous synthesis of vitamin D. It is also proposed that ability to pigment in response to UVR will influence susceptibility to prostate cancer through its effects on vitamin D synthesis. We wished to determine first, whether ability to pigment, as assessed by skin type, influences the extent of exposure to UVR, secondly, whether skin type is associated with prostate cancer susceptibility and thirdly, whether such an effect is mediated by the extent of UVR exposure. We studied 453 prostatic adenocarcinoma and 312 benign prostatic hypertrophy (BPH) patients using a validated questionnaire to assess two parameters of exposure; months of cumulative exposure per year and adult sunbathing score. We used analysis of variance to show that cancer cases with sun-sensitive skin (skin type 1) had lower cumulative exposure per year (P = 0.014) and sunbathing scores (P < 0.0001) than those with type 4, possibly because of a tendency to avoid exposure. Further, cumulative exposure per year and sunbathing score were significantly lower in cancer compared with BPH patients (P < 0.001 and P < 0.001, respectively). While the proportion of subjects with skin types 1 and 2 was lower in cancer than BPH patients, these were not significantly different (logistic regression analysis, skin type 1 versus type 4; P = 0.11). We used recursive partitioning to determine if skin type influenced susceptibility to prostate cancer in subgroups stratified by exposure. Analysis of the data showed that in men with low sunbathing scores, skin type 1 conferred protection compared with skin types 2-4 (OR = 4.78, 95% CI 3.01-8.25, P < 0.0009). These findings indicate that susceptibility to prostate cancer is in part determined by extent of exposure to UVR and that ability to pigment mediates this effect.
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PMID:Susceptibility to prostate cancer: studies on interactions between UVR exposure and skin type. 1272

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

1,25-Dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)), inhibits proliferation of a variety of cell types including adenocarcinoma of the prostate. We have previously shown that 1,25-(OH)(2)D(3) increases the stability of the cyclin-dependent kinase inhibitor p27(KIP1), decreases cyclin-dependent kinase 2 (CDK2) activity, and promotes G(1) phase accumulation in human prostate cancer cells. These effects correlate with cytoplasmic relocalization of CDK2. In this study, we investigated the role of CDK2 cytoplasmic relocalization in the antiproliferative effects of 1,25-(OH)(2)D(3). CDK2 was found to be necessary for prostate cancer cell proliferation. Although induced by 1,25-(OH)(2)D(3), the cyclin-dependent kinase inhibitor p27(KIP1) was dispensable for 1,25-(OH)(2)D(3)-mediated growth inhibition. Reduction in CDK2 activity by 1,25-(OH)(2)D(3) was associated with decreased T160 phosphorylation, a residue whose phosphorylation in the nucleus is essential for CDK2 activity. Ectopic expression of cyclin E was sufficient to overcome 1,25-(OH)(2)D(3)-mediated cytoplasmic mislocalization of CDK2 and all antiproliferative effects of 1,25-(OH)(2)D(3), yet endogenous levels of cyclin E or binding to CDK2 were not affected by 1,25-(OH)(2)D(3). Similarly, knockdown of the CDK2 substrate retinoblastoma, which causes cyclin E up-regulation, resulted in resistance to 1,25-(OH)(2)D(3)-mediated growth inhibition. Human prostate cancer cells resistant to growth inhibition by 1,25-(OH)(2)D(3) but retaining fully functional vitamin D receptors were developed. These cells did not exhibit 1,25-(OH)(2)D(3)-mediated cytoplasmic relocalization of CDK2. Targeting CDK2 to the nucleus of 1,25-(OH)(2)D(3)-sensitive cancer cells blocked G(1) accumulation and growth inhibition by 1,25-(OH)(2)D(3). These data establish central roles for CDK2 nuclear-cytoplasmic trafficking and cyclin E in the mechanism of 1,25-(OH)(2)D(3)-mediated growth inhibition in prostate cancer cells.
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PMID:Nuclear targeting of cyclin-dependent kinase 2 reveals essential roles of cyclin-dependent kinase 2 localization and cyclin E in vitamin D-mediated growth inhibition. 2014 22