Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, we completed three chronic studies in rats indicating that cadmium exposure can induce tumours of the prostate. In the first study, s.c. cadmium exposure increased prostatic tumour incidence only at doses below the threshold for cadmium induction of testicular dysfunction (5.0 mumol/kg). In a second study, prostatic tumours were elevated at higher doses of cadmium (30 mumol/kg, s.c.) if testicular dysfunction was prevented by zinc treatment. Finally, dietary cadmium (25-200 micrograms/g) increased prostatic neoplastic lesions. Thus it appears that cadmium produces prostatic tumours only if testicular function is maintained. Accumulation and retention of prostatic cadmium appears to be highly androgen-dependent. Furthermore, metallothionein, a protein associated with tolerance to cadmium, may be deficient in the rat prostate, and the prostatic metallothionein gene, at least in the ventral lobe, may be unresponsive to metal stimuli. The finding of prostatic cancer in cadmium-treated rats clearly supports a possible role for exposure to cadmium in human prostatic cancer.
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PMID:Cadmium exposure in rats and tumours of the prostate. 130 66

We analyzed metallothionein (MT) in rat prostates by gel filtration and radioimmunoassay. The concentration of MT in the prostate, kidney and liver of cadmium-induced rats was measured. The concentration of MT was also measured in normal prostate, benign prostatic hyperplasia, prostate cancer and the prostatic fluids from various prostatic diseases in humans. MT was detected in rat prostates by gel filtration and radioimmunoassay. The concentration of MT (micrograms/g wet tissue) was 0.3 +/- 0.1 (S.D.) in the ventral lobe, 30.4 +/- 24.0 in the lateral lobe, 5.2 +/- 0.9 in the dorsal lobe, 25.0 +/- 6.4 in the kidney and 2.0 +/- 1.5 in the liver of the rat control group. Change in MT content in CdCl2-induced organs increased quantitatively with the dose administered. The concentration of MT (micrograms/g wet tissue) in human prostate was 99.3 +/- 121.8 in the peripheral zone (PZ), 12.0 +/- 8.5 in the preprostatic region (PR), 7.3 +/- 3.1 in the central zone (CZ), 17.5 +/- 15.0 in benign hyperplastic nodules (A) and 4.2 +/- 0.5 in cancer tissue (CA). MT concentration in PZ was very high and that of CA, low (p less than 0.05). MT concentration in prostatic fluids (ng/mg protein) was 11.5 +/- 5.7 in normal patients, 3.8 +/- 2.3 in acute prostatitis, 6.5 +/- 3.7 in chronic prostatitis with pyuria, 39.6 +/- 3.9 in chronic prostatitis without pyuria and 16.9 +/- 3.0 in benign prostatic hyperplasia. We concluded that MT in the prostate is induced by heavy metals and secreted into prostatic fluid. Possibly, it is a marker of secretory function in the prostate.
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PMID:Metallothionein of prostatic tissues and fluids in rats and humans. 137 27

The LNCaP human prostate cancer cell line is dependent on androgen for in vitro growth. To discover genes that may be responsible for progression of prostate cancer from hormone dependence to hormone independence, we transfected LNCaP cells with expression vectors that contained either the v-rasH or c-rasH gene under the control of the cadmium (Cd2+)-inducible human metallothionein-IIA promoter. Numerous derivative cell lines were isolated which manifested inducible expression of rasH p21 protein when the cells were treated with Cd2+. None of the cell lines transfected with c-rasH were found to have an altered growth phenotype. Several derivative cell lines expressing inducible v-rasH manifested hormone-independent growth in culture when treated with 10(-7) M Cd2+ . Cd2+ induction of v-rasH p21 was also shown to increase anchorage-independent colony formation of the v-rasH-expressing cell lines tested. Expression of a dominant mutated oncogene can change the hormone-dependent growth phenotype of prostate cancer cells.
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PMID:v-rasH expression confers hormone-independent in vitro growth to LNCaP prostate carcinoma cells. 203 42

Prostatic cancer is a common and frequently lethal malignant disease. In the United States and other countries the incidence and mortality rate of prostate cancer continue to rise. Cancer of the prostate has an extremely complex etiology and appears dependent on a variety of factors, making linkage to a single factor very difficult to detect. Cadmium is a metallic toxin of great environmental and occupational concern. Cadmium exposure has been associated with human prostatic cancer in some, but not all, epidemiologic studies. Some studies indicate that tissue levels of cadmium in the human prostate correlate with malignant disease. Any association between cadmium and prostatic cancer has been controversial, in large part because of a previous lack of relevant animal models. However, several chronic studies in rats revealing a correlation between cadmium exposure and prostatic tumors have been published over the last several years. These include a study of oral cadmium exposure, a route extremely relevant to human exposure. Several of these chronic studies indicate a hormonal dependence of cadmium-induced prostate cancer. Other supportive work continues to accumulate, such as studies showing in vitro malignant transformation of prostatic epithelial cells with cadmium exposure. In addition, there are indications that the primary biologic tolerance system for cadmium (i.e., the metallothionein gene) may be only poorly active in the specific lobes of the rat prostate in which cadmium induces tumors. The induction in rats of prostate cancer by cadmium treatment clearly supports, but does not definitively establish, a possible role for cadmium as an etiological agent in human prostate cancer. Further research, however, will be required to establish the precise role of cadmium in this important human malignancy.
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PMID:Cadmium and prostate cancer. 796 37

The effects of various means of interfering with androgen action on rat coagulating gland, ventral prostate, lateral type 1 prostate, lateral type 2 prostate, and dorsal prostate were examined morphologically and quantitatively by assessing DNA content, wet weight, protein content, and zinc concentrations. Adult male Sprague-Dawley rats were subjected to 2 weeks of interfering with androgen action by treatment with Leuprolelin (a luteinizing hormone-releasing hormone analog), Finasteride (a 5 alpha-reductase inhibitor), or diethylstilbestrol (DES), or by physical castration. For all prostatic lobes, inhibition of 5 alpha-reductase elicited the smallest reduction in prostatic wet weight, DNA and protein contents, and zinc concentration. The most profound reductions in all parameters were elicited by castration. Treatments with DES and Leuprolelin gave intermediate effects with DES being the more effective in reducing all parameters in all prostatic lobes. Morphological changes elicited by all forms of androgen blockade were reduction of epithelial height, relative increase of connective tissue, reduction in ductal diameter, length, and number. The order of effectiveness of the various treatments on morphological features was as described above. While all forms of androgen blockade elicited similar effects throughout the prostate, differences in response to all forms of interference with androgen action were observed in different lobes of the prostate with regard to wet weight, DNA and protein contents, and zinc concentration as well as morphological effects. Regressive changes at the morphological level were particularly striking in the coagulating gland and ventral prostate, and indistinct in the lateral type 2 prostate. Prostatic zinc concentration in both normal and androgen-deprived rats was the highest in the lateral type 2 prostate and was reduced by interfering with androgen action to the greatest extent in the dorsolateral prostate (lateral type 1 and type 2, and dorsal prostate). The distribution of zinc correlated with the expression of metallothionein, which was detected by immunocytochemistry only in the lateral type 2 prostate of both normal and androgen deprived rats. Intraprostatic heterogeneity of zinc and metallothionein expression emphasizes interlobar differences in biological function within the rat prostate. The mechanism of development of regional heterogeneity within the prostate may shed light on the pathogenesis of prostatic proliferative diseases (prostatic hyperplasia and prostatic cancer) that initially owe their development to focal changes within large cell populations.
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PMID:Influence of diethylstilbestrol, Leuprolelin (a luteinizing hormone-releasing hormone analog), Finasteride (a 5 alpha-reductase inhibitor), and castration on the lobar subdivisions of the rat prostate. 868 49

Prostate carcinoma is the second leading cause of death from malignancy in men in the United States. Prostate cancer cells express type I insulin-like growth factor receptor (IGF-IR) and prostate cancer selectively metastazises to bone, which is an environment rich in insulin-like growth factors (IGFs), thereby supporting a paracrine action for cancer cell proliferation. We asked whether the IGF-IR is coupled to tumorigenicity and invasion of prostate cancer. When rat prostate adenocarcinoma cells (PA-III) were stably transfected with an antisense IGF-IR expression construct containing the ZnSO4-inducible metallothionein-1 transcriptional promoter, the transfectants expressed high levels of IGF-IR antisense RNA after induction with ZnSO4, which resulted in dramatically reduced levels of endogenous IGF-IR mRNA. A significant reduction in expression both of tissue-type plasminogen activator and of urokinase-type plasminogen activator occurred in PA-III cells accompanying inhibition of IGF-IR. Subcutaneous injection of either nontransfected PA-III or PA-III cells transfected with vector minus the IGF-IR insert into nude mice resulted in large tumors after 4 weeks. However, mice injected with IGF-IR antisense-transfected PA-III cells either developed tumors 90% smaller than controls or remained tumor-free after 60 days of observation. When control-transfected PA-III cells were inoculated over the abraded calvaria of nude mice, large tumors formed with invasion of tumor cells into the brain parenchyma. In contrast, IGF-IR antisense transfectants formed significantly smaller tumors with no infiltration into brain. These results indicate an important role for the IGF/IGF-IR pathway in metastasis and provide a basis for targeting IGF-IR as a potential treatment for prostate cancer.
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PMID:Antisense RNA to the type I insulin-like growth factor receptor suppresses tumor growth and prevents invasion by rat prostate cancer cells in vivo. 869 80

We constructed expression vectors containing either rat fibroblast growth factor (FGF)-1 for FGF-2 cDNA cloned in either the sense orientation or antisense orientation relative to the metallothionein promoter of plasmid pMTneo.1. Stable AXC/SSh rat prostate cancer cell transfectants expressing either chimeric FGF-1-sense, chimeric FGF-1-antisense, or chimeric FGF-2-antisense transcripts were obtained. Stable transfectants expressing chimeric FGF-2-sense transcripts were not obtained. Control, sense, and antisense transfectants expressed endogenous FGF-1 and endogenous FGF-2 transcripts, implying that transfection did not eliminate endogenous FGF transcripts. Control transfectants and sense transfectants contained FGF-1 isoforms having a mass of 16.4 or 17.3 kDa and FGF-2 isoforms having a mass of 17, 19.5, or 21.5 kDa. Significantly, adult AXC/SSh rat prostate contained only the 17.3 kDa FGF-1 isoform and the 17 kDa FGF-2 isoform, indicating that neoplastic transformation was associated with elaboration of novel, prostate epithelial cell-derived FGF-2 isoforms. FGF-1 antisense RNA expression eliminated transfectant FGF-1 isoforms without affecting FGF-2 isoform content. Similarly, FGF-2-antisense RNA expression eliminated the transfectant 21.5 kDa FGF-2 isoform, diminished the 19.5 kDa FGF-2 isoform content, and reduced the 17 kDa FGF-2 isoform content to barely detectable levels without affecting the FGF-1 isoform content. This established that FGF-antisense RNAs specifically inhibited translation of cognate, endogenous FGF transcripts. Doubling times of control transfectants and sense transfectants were indistinguishable and were not affected by including FGF-1 or FGF-2 in the culture medium. Doubling times of FGF-1-antisense or FGF-2-antisense transfectants were 1.3- to 1.4-fold greater than those of control transfectants or sense transfectants, and either exogenous FGF-1 or exogenous FGF-2 decreased antisense transfectant doubling times to values indistinguishable from those of control transfectants or sense transfectants. This established that with regard to prostate cancer cell proliferation: (a) endogenous FGF-1 cannot substitute for endogenous FGF-2 eliminated by FGF-2-antisense RNA expression; and (b) endogenous FGF-2 cannot substitute for endogenous FGF-1 eliminated by FGF-1-antisense RNA expression. In contrast, either exogenous FGF-1 or exogenous FGF-2 decreased antisense transfectant doubling time. The results of these studies establish that endogenous FGF-1 and endogenous FGF-2 modulate prostate cancer cell proliferation and imply that FGF-1 and FGF-2 of endogenous and exogenous origin conjointly control aspects of prostate cancer cell homeostasis. Our findings suggest complex interaction between components of prostate cancer cell regulatory processes and endogenously produced and exogenously accessible FGF-1 and FGF-2.
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PMID:Endogenous fibroblast growth factor-1 or fibroblast growth factor-2 modulate prostate cancer cell proliferation. 873 67

Because the up-regulation of telomerase in most cancer tissues is considered to be responsible for the unlimited proliferation of cancer cells, suppression of telomerase activity is an attractive potential target for cancer therapy. The mechanism for the activation of telomerase in cancer cells, however, is still unclear. In the present study, we demonstrated that Zn induces an enhancement of telomerase activity in the human renal cell carcinoma (NRC-12) and prostatic cancer (DU145) cell lines. The maximum elevation of the activity was observed 6 hr after treatment with 100 microM Zn; it was diminished by the addition of either metal chelator or cycloheximide. Other metals such as Cd and Cu also enhanced telomerase activity but to a lesser extent, and no correlation between the activation of telomerase and the induction of metallothionein was observed. Our findings provide the first evidence that metals, especially Zn, can modulate telomerase activity in cancer cells.
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PMID:Modulation of telomerase activity by zinc in human prostatic and renal cancer cells. 1064 48

The third isoform of metallothionein (MT-3) is overexpressed in some breast cancers and its expression is associated with a poor disease outcome. In the PC-3 prostate cancer cell line, MT-3 expression has been shown to inhibit cell growth and increase drug resistance. The goal of the present study was to determine if MT-3 overexpression would influence the growth of human breast cancer cell lines. To determine this, the coding sequence of the MT-3 gene was stably transfected into two estrogen receptor positive (MCF-7 and T-47D) and two estrogen receptor negative cell lines (Hs578T and MDA-MB-231) having no basal expression of MT-3. Cell growth was determined by counting DAPI-stained nuclei, cadmium resistance by the colony formation assay, MT mRNA expression by RT-PCR, and MT protein by immuno-blot. It was demonstrated that MCF-7 and Hs578T cells that overexpress the MT-3 gene were growth inhibited compared to untransfected cells. In contrast, T-47D and MDA-MB-231 cells that overexpress MT-3 were not growth inhibited. Stable transfection of the MT-1E gene had no effect on the growth of any of the four cell lines. It was also demonstrated that the overexpression of both MT-3 and MT-1E only increased the resistance of MCF-7 cells to Cd(+2). In all instances, stable transfection of the MT-3 or MT-1E gene had no effect on the expression of the other MT isoforms. The study shows that MT-3 can influence the growth of some breast cancer cell lines.
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PMID:Stable transfection and overexpression of metallothionein isoform 3 inhibits the growth of MCF-7 and Hs578T cells but not that of T-47D or MDA-MB-231 cells. 1290 21

Prostate glands contain heavy metals such as zinc and cadmium, and epidemiological studies showed that both metals were associated with prostate cancer development. To understand the heavy metal metabolism in prostate glands, we investigated the regulation of metallothionein (MT), metal-responsive promoter element-binding transcription factor (MTF) and zinc transporter (ZnT) in human prostate cells and tissues. Growth of human prostate cancer cells, LNCaP and PC-3 cells, was suppressed by zinc or cadmium treatment in a dose-dependent manner. LNCaP cells expressed MT-1A, 1X and 2A mRNA, and PC-3 cells expressed MT-1X and 2A mRNA. Zinc or cadmium treatment up-regulated MTs, MTF-1 and ZnT-1 gene expression levels in both cell lines. In PC-3 cells, ZnT-1 protein was detected, and was up-regulated by the metal treatment. Human prostate cancer tissues expressed significantly lower levels of ZnT-1 gene in comparison with hyperplastic tissues. We demonstrated the ZnT-1 expression in human prostate for the first time. The present study showed that heavy metal-metabolizing proteins were involved in human prostate homeostasis, and that the metal metabolizing system might be different in malignant tissues.
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PMID:Regulation of metallothionein and zinc transporter expression in human prostate cancer cells and tissues. 1456 74


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