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)

In the normal prostate, transforming growth factor-beta 1 (TGF-beta 1) inhibits epithelial cell growth and is associated with apoptosis. The role of TGF-beta 1 in prostate cancer remains, however, unclear. In this work, the expression of TGF-beta receptor type I and II (TGF beta-RI and TGF beta-RII) in the Dunning R3327 PAP adenocarcinoma was studied, after castration and oestrogen treatment. Since castration induces apoptosis in the rat ventral prostate (VP) [21], but not in the Dunning R3327 PAP tumour [46], the TGF-beta receptor levels in the tumour were compared to the receptor levels in the VP. Methods used were competitive reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. In the VP, TGF beta-RI and TGF beta-RII expressions were increased after castration, indicating a negative regulation of TGF beta receptors by androgens. In the Dunning tumour, TGF beta-RI and TGF beta-RII levels were elevated and only TGF beta-RI showed a clear-cut increase after castration. The receptors were located in epithelial and smooth muscle cells in the VP and mainly in epithelial cells in the Dunning tumour. In conclusion, the elevated TGF beta receptor levels and the diminished androgen regulation of TGF beta-RII in the tumour distinguish the Dunning R3327 PAP tumour from the normal prostate and need to be further elucidated.
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PMID:Expression of transforming growth factor-beta receptor type I and type II in rat ventral prostate and Dunning R3327 PAP adenocarcinoma in response to castration and oestrogen treatment. 914 76

Activin A, a homodimer of the betaA subunit of inhibin, is a member of the TGF-beta family. It is a multifunctional molecule regulating the growth, differentiation, and survival of a variety of cells. Treatment with activin A to an androgen-sensitive human prostatic cancer cell line LNCaP resulted in growth and morphological change and those were accompanied by up-regulation of prostatic differentiation markers prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP). In addition, the expression of androgen receptor was also enhanced by activin treatment. These results suggest that activin has significant influence on LNCaP cells.
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PMID:Regulation of growth and prostatic marker expression by activin A in an androgen-sensitive prostate cancer cell line LNCAP. 917 76

Transforming growth factor-beta (TGF-beta1) is a potent negative regulator of cell growth that transduces signals through interactions with type I and II receptors. Abnormal expression and mutational alterations of these receptors have been observed in several human malignancies. In this study, we investigated the expression of the two types of TGF-beta1 receptors, R-I and R-II, in a normal human prostate, primary prostate adenocarcinoma and lymph nodes with metastatic deposits. Expression of receptor proteins was examined by immunohistochemical analysis in paraffin-embedded prostatic tissue sections, and mRNA expression was determined by Northern blot and RT-PCR analysis. Uniformly strong immunoreactivity for both TGF-beta receptor proteins, R-I and R-II, was exclusively localized to the prostatic glandular epithelium of normal prostates. In contrast, tumor epithelial cells in primary and metastatic prostatic cancer specimens exhibited a weak heterogeneous immunoreactivity for both R-I and R-II receptors; 25% of primary prostatic tumors and 45% of the lymph nodes with metastases were totally negative for R-I and R-II expression, while the rest exhibited a significantly reduced immunoreactivity for both types of receptors compared to the normal prostate (p < 0.05). Moreover, there was a significant decrease in the expression of R-I and R-II mRNA, in all 20 primary prostatic tumors and 4 lymph nodes positive for metastases, indicating that the decreased protein expression was due to down-regulation of gene expression for the two receptors. Our findings imply that decreased expression of TGF-beta1 type I and type II receptors might be involved in prostate tumorigenesis.
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PMID:Down-regulation of protein and mRNA expression for transforming growth factor-beta (TGF-beta1) type I and type II receptors in human prostate cancer. 917 10

Prostate cancer and benign tumors of the prostate are the two most common neoplastic diseases in men in the United States, however, research on their causes and treatment has been slow because of the difficulty in obtaining fresh samples of human tissue and a lack of well characterized cell lines which exhibit growth and differentiation characteristics of normal prostatic epithelium. Non-neoplastic adult human prostatic epithelial cells from a white male donor were immortalized with human papillomavirus 18 which resulted in the establishment of the RWPE-1 cell line. Cells from the RWPE-1 cell line were further transformed by v-Ki-ras to establish the RWPE-2 cell line. The objectives of this study were to: (1) establish the prostatic epithelial origin and androgen responsiveness of RWPE-1 and RWPE-2 cell lines; (2) examine their response to growth factors; and (3) establish the malignant characteristics of the RWPE-2 cell line. Immunoperoxidase staining showed that both RWPE-1 and RWPE-2 cells express cytokeratins 8 and 18, which are characteristic of luminal prostatic epithelial cells, but they also coexpress basal cell cytokeratins. These cell lines show growth stimulation and prostate specific antigen (PSA) and androgen receptor (AR) expression in response to the synthetic androgen mibolerone, which establishes their prostatic epithelial origin. Both cell lines also show a dose-dependent growth stimulation by EGF and bFGF and growth inhibition when exposed to TGF-beta, however, the transformed RWPE-2 cells are less responsive. RWPE-1 cells neither grow in agar nor form tumors when injected into nude mice with or without Matrigel. However, RWPE-2 cells form colonies in agar and tumors in nude mice. In the in vitro invasion assay, RWPE-1 cells are not invasive whereas RWPE-2 cells are invasive. Nuclear expression of p53 and Rb proteins was heterogeneous but detectable by immunostaining in both cell lines. The RWPE-1 cells, which show many normal cell characteristics, and the malignant RWPE-2 cells, provide useful cell culture models for studies on prostate growth regulation and carcinogenesis.
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PMID:Androgen responsive adult human prostatic epithelial cell lines immortalized by human papillomavirus 18. 921 5

The role of bropirimine in prostate cancer remains unexplored. To address the efficacy of this immune modulator as neoadjuvant therapy we utilized the orthotopic placement of the Dunning AT-3 tumor. 2.4-2.6 x 10(6) Dunning AT-3 cells were injected into the ventral prostates of 50 Copenhagen X Fischer rats. Animals were then divided into 5 groups consisting of: 1) untreated controls; 2) those treated with ventral prostatectomy alone (performed 10-12 days following tumor cell inoculation); 3) those treated with ventral prostatectomy plus bropirimine (10 mg/kg) on postimplantation days 1, 3, 5, 10 and 11; 4) those treated with ventral prostatectomy plus bropirimine (100 mg/kg), at the same schedule; and 5) those treated with ventral prostatectomy plus bropirimine (500 mg/kg), at the same schedule. Animals were sacrificed 10 days after prostatectomy, autopsied, and residual disease was weighed. Prostate weights upon removal following neoadjuvant treatment and residual disease remaining after 20-22 days were expressed in grams (g). Following prostatectomy, mean prostate weights were: Group 2, 0.67 +/- 0.11; Group 3, 0.53 +/- 0.11; Group 4, 0.54 +/- 0.12; Group 5, 0.44 +/- 0.09. The effect of bropirimine was significant (p = 0.0001) by multiple regression analysis. In addition, mean residual tumor weights (expressed in grams) after 20-22 days were: Group 1, 12.7 +/- 1.9; Group 2, 6.7 +/- 4.8; Group 3, 5.2 +/- 5.9; Group 4, 3.8 +/- 3.5; and Group 5, 2.8 +/- 3.5. The effect of bropirimine was not significant (p = 0.07) by multiple regression analysis. However, prostatectomy alone, by Student's test, significantly (p = 0.04) reduced residual mean tumor weights by 47% and the additional effect of bropirimine upon residual disease was significant (p = 0.038) if a Chi-square analysis is applied. Finally, a multivariate analysis of the overall effect of bropirimine in rats treated with prostatectomy was significant (p = 0.002). The effect of bropirimine on expression of proliferating cell nuclear antigen (PCNA) and transforming growth factor beta 1 (TGF-beta 1) was also evaluated immunohistochemically and expression of both tumor markers was significantly reduced (p < 0.05). We conclude that bropirimine may have a role as a neoadjuvant therapy when combined with prostatectomy.
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PMID:Bropirimine as neoadjuvant therapy decreases residual disease and expression of markers PCNA and TGF-beta 1 in a rat orthotopic prostate adenocarcinoma. 922 52

Both hyaluronidase and transforming growth factor (TGF)-beta 1 play a significant role in the development of prostate cancer. In this study, the regulation of tumor necrosis factor (TNF)-mediated cell death by hyaluronidase and TGF-beta 1 was investigated. Preexposure of L929 fibroblasts, prostate LNCaP cells, and epithelial Mv 1 Lu cells to hyaluronidase for a minimum of 12 h resulted in significant enhancement of cell death by TNF. Phosphorylation of p42 and p44 mitogen-activated-protein (MAP) kinases was found by stimulation of L929 cells with hyaluronidase for 30 min, indicating that the Raf/MAP kinase-extracellular signal-regulating protein kinase (MEK)/ MAP kinase pathway was activated. However, blocking the activation of upstream MAP kinase kinase (MEK 1 and 2 kinase) by PD-98059 failed to inhibit the hyaluronidase-enhanced TNF killing of cells, suggesting that hyaluronidase-mediated degradation of extracellular matrix and membrane components may elicit multiple signaling pathways. As a potent stimulator of extracellular matrix protein synthesis, TGF-beta 1 blocked the hyaluronidase-enhanced death of L929 and LNCaP cells mediated by TNF. TGF-beta 1 activated protein-tyrosine kinases in L929 cells, in which the tyrosine kinase inhibitors lavendustin A and tyrphostin blocked the activation as well as the TGF-beta 1 inhibition of hyaluronidase effects. Functional antagonism was also observed between hyaluronidase and TGF-beta 1 in cell growth regulation. For example, TGF-beta 1-mediated suppression of epithelial Mv 1 Lu cell growth was abolished by hyaluronidase. Overall, it is demonstrated in this study that hyaluronidase reciprocally antagonized TGF-beta 1 in the modulation of cell proliferation and TNF-mediated death.
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PMID:Hyaluronidase enhancement of TNF-mediated cell death is reversed by TGF-beta 1. 943 5

TGF-beta1 is a potent negative regulator of cell growth that transduces signals through interaction with type I and type II receptors that form a heteroduplex. Abnormal expression and mutational alterations of these receptors have recently been shown in several human malignancies. In previous studies, we have demonstrated reduced expression of both types of transforming growth factor (TGF) beta1 receptors in human prostate tumors. In this study, using the human prostate cancer cell line, LNCaP, which is refractory to TGF-beta1 and lacks type II receptor (R-II), we investigated whether overexpression of the R-II receptor can restore sensitivity to the negative growth effects of TGF-beta1. LNCaP cells were transfected with plasmid containing the full length of human TGF-beta R-II receptor cDNA sequence. Stable transfectant clones were selected for R-II mRNA and protein expression by Northern and Western analyses, respectively. The effect of TGF-beta on LNCaP R-II overexpressing clones was examined on the basis of: (a) growth inhibition (cell number); (b) DNA synthesis using the [3H]thymidine incorporation assay; (c) induction of cyclin-dependent-kinase inhibitors, p21WAF-1/Cip1, p27Kip1, and p15; and (d) colony-forming ability in soft agar. Both the cell number and the rate of DNA synthesis of R-II-overexpressing clones were significantly suppressed by exogenous TGF-beta1 in a dose-dependent manner, compared with control cell lines. Treatment of R-II cloned transfectants with TGF-beta1 induced a G1 arrest, which was accompanied by a transient increase in p21WAF-1/Cip1 and p27Kip1 expression at the mRNA and protein level. Furthermore, the LNCaP R-II transfectants analyzed exhibited a markedly reduced colony-forming ability. Our results indicate that overexpression of TGF-beta1 R-II receptor in LNCaP prostate cancer cells caused tumor growth inhibition by restoring the TGF-beta signaling mechanism and TGF-beta1 sensitivity.
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PMID:Overexpression of transforming growth factor (TGF) beta1 type II receptor restores TGF-beta1 sensitivity and signaling in human prostate cancer cells. 948 55

Transforming growth factor-beta 1 (TGF-beta 1) is a pleiotrophic growth factor in carcinogenesis and regulars multiple cell functions. We wanted to evaluate the diagnostic meaning of TGF-beta 1 plasma levels in patients with a biopsy proven prostate cancer. The TGF-beta 1 blood level was analysed in 394 patients. In 242 patients (group I) the blood was taken before any prostate manipulation and biopsy. The TGF-beta 1 plasma concentrations were almost similar in the group of patients with a prostate cancer (n = 157) and patients with a benign prostate hyperplasia (n = 85; 14,258 pg/ml versus 14,658 pg/ml, SD 10,516 pg/ml). In 152 patients the blood was taken 6-12 months after radical prostatectomy (group II). There was no significant difference between the patients with a PSA-progress and without PSA-progress after. Our results suggest that TGF-beta 1 plasma levels can not be used to distinguish between patients with prostate cancer and benign prostate hyperplasia.
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PMID:[Plasma TGF-beta1 concentrations in patients with prostate carcinoma or benign prostatic hyperplasia]. 956 35

LNCaP is an androgen-responsive human prostate cancer cell line that has a defective gene for ALK-5, the conventional TGF-beta receptor type I. Yet, these cells respond to exogenous TGF-beta 1 under appropriate concentrations of dihydrotestosterone (DHT). Because a heteromeric complex composed of type I and type II receptor is required for TGF-beta signaling, the expression of these receptors was investigated in LNCaP cells at following concentrations of DHT-0, 0.1, and 100 nM. These concentrations were selected because they represent the zero DHT control in which LNCaP cells are not sensitive to TGF-beta 1, the proliferative dose of DHT in which these cells are sensitive to exogenous TGF-beta 1, and the growth-arrest dose of DHT in which LNCaP exhibits signs of TGF-beta signaling but are insensitive to exogenous TGF-beta 1, respectively. Results of Western blot analysis showed that LNCaP cells express an increased level of type II receptor at 0.1 nM DHT, the TGF-beta 1-sensitive dose. However, results of competitive quantitative RT-PCR demonstrated that DHT did not significantly change the level of type II receptor mRNA, suggesting that DHT modulates the level of type II receptor at the posttranscriptional level. In contrast, ALK-5 was not detected in these cells by either Western blot analysis or RT-PCR at all concentrations of DHT used in this study. Subsequently, the expression of ALK-1, -2, and -4 in LNCaP cells was examined because these proteins have been shown to bind TGF-beta 1 in vitro. ALK-1 and -2 were detected in these cells. Further analysis by competitive quantitative RT-PCR and Western blot demonstrated that DHT did not affect the level of expression of ALK-1 and -2 in LNCaP cells. These observations, taken together, demonstrate that ALK-5 is not required for TGF-beta 1 signaling and that there may be alternative mechanism(s) for TGF-beta 1 signal transduction in some systems.
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PMID:The conventional transforming growth factor-beta (TGF-beta) receptor type I is not required for TGF-beta 1 signaling in a human prostate cancer cell line, LNCaP. 963 23

In previous studies we demonstrated that the growth of human prostatic adenocarcinoma is associated with aberrant accumulation of transforming growth factor (TGF) beta1, a growth factor that has been shown to be a potent inhibitor of epithelial cell proliferation. We investigated the expression of TGF-beta receptor II (TGFbetaR-II) in benign prostate tissue and in prostate cancer using standard immunohistochemical techniques. Quantitation of immunopositivity for TGFbetaR-II was assessed on a visual analogue scale ranging from 0 (absence of staining) to 4+ (intensely positive staining). All of the benign glandular epithelia stained intensely, either 3+ or 4+, representative of the ubiquitous nature of TGFbetaR-II in normal tissue. Overall, staining was reduced in prostate cancer sections, and there was progressively diminished staining as the histological grade of the cancer increased (P < 0.01, Kruskal-Wallis test). This immunohistochemical study indicates that a decline in the levels of TGFbetaR-II is correlated with advancing histological aggressiveness of the cancer and suggests that aberrant TGFbetaR-II function may play a role in human prostate carcinogenesis.
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PMID:Reduced levels of transforming growth factor beta receptor type II in human prostate cancer: an immunohistochemical study. 981 13


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