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)

Phenylbutyrate (PB) is a histone deacetylase inhibitor that has been shown to induce differentiation and apoptosis in various cancer cell lines. Although these effects are most likely due to modulation of gene expression, the specific genes and gene products responsible for the effects of PB are not well characterized. In this study, we used cDNA expression arrays and Western blot to assess the effect that PB has on the expression of various cancer and apoptosis-regulatory gene products. We show that PB attenuates the expression of the apoptosis antagonist Bcl-X(L), the double-strand break repair protein DNA-dependent protein kinase, the prostate progression marker caveolin-1, and the pro-angiogenic vascular endothelial growth factor. Furthermore, PB was found to act in synergy with ionizing radiation to induce apoptosis in prostate cancer cells. Taken together, our results point to the possibility that PB may be an effective anti-prostate cancer agent when used in combination with radiation or chemotherapy and for the inhibition of cancer progression.
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PMID:Phenylbutyrate attenuates the expression of Bcl-X(L), DNA-PK, caveolin-1, and VEGF in prostate cancer cells. 1157 33

Caveolin-1, a structural component of caveolae, is overexpressed in metastatic and androgen-resistant prostate cancer and highly expressed in tumor-associated endothelial cells. The mouse cav-1 promoter was cloned and placed upstream of the HSV-tk gene in an adenoviral vector (Adcav-1tk) and compared with a cytomegalovirus (CMV) or Rous sarcoma virus (RSV) promoter-driven HSV-tk, AdCMVtk and AdRSVtk vectors, respectively. Mouse and human prostate cancer cells and mouse endothelial cells were infected with Adcav-1tk, AdCMVtk or control vectors without the HSV-tk gene (Adcav-1 and AdCMV) and subsequently treated with ganciclovir (GCV). GCV-mediated in vitro cytotoxicity induced by the Adcav-1tk vector was comparable to that for AdCMVtk in multiple mouse and human prostate cancer cell lines. To evaluate the activity of Adcav-1tk in vivo, orthotopic mouse prostate cancer tumors were generated with RM-9 cells and injected in situ with Adcav-1tk, AdCMVtk, AdRSVtk, or AdCMVbetagal (control) and treated with GCV. All three HSV-tk transducing vectors produced statistically significant reductions in wet weight and increased apoptotic indices compared with the control vector. However, only Adcav-1tk produced significant necrosis, and only Adcav-1tk and AdRSVtk caused significant decreases in microvessel density. In conclusion, Adcav-1tk demonstrated efficacy in vitro and in vivo in preclinical models of prostate cancer. Our results suggest that the cav-1 promoter may have unique benefits in targeting gene therapy to prostate cancer and its associated vasculature.
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PMID:In situ prostate cancer gene therapy using a novel adenoviral vector regulated by the caveolin-1 promoter. 1175 29

Prostatic epithelial cells that are capable of surviving in the absence of androgenic steroids were found to express protein kinase Cepsilon (PKCepsilon), an oncogenic protein capable of promoting autocrine cell-signaling events. Gene transfer experiments demonstrated that PKCepsilon overexpression was sufficient to transform androgen-dependent LNCaP cells into an androgen-independent variant that rapidly initiated tumor growth in vivo in both intact and castrated male nude mice. This transformation was associated with an accelerated rate of androgen-independent LNCaP cell proliferation, resistance to apoptosis, hyperphosphorylation of the mitogen-activated protein kinase extracellular signal-regulated kinase and transcriptional repressor protein retinoblastoma, and increased expression of E2F-1 and other 5'-cap-dependent mRNAs, including the G(1) cyclins, c-myc, and caveolin-1. Coimmunoprecipitation experiments indicated that PKCepsilon was associated with members of the extracellular signal-regulated kinase signaling cascade and the scaffolding protein caveolin-1. Caveolin-1, produced by LNCaP cells overexpressing PKCepsilon, was released into the medium, possibly through a Golgi-independent route, and significant growth inhibition was observed when these cells were cultured in the presence of an anti-caveolin-1 antiserum. Finally, antisense experiments established that endogenous PKCepsilon plays an important role in regulating the growth and survival of androgen-independent prostate cancer cells. This study provides several independent lines of evidence supporting the hypothesis that PKCepsilon expression may be sufficient to maintain prostate cancer growth and survival after androgen ablation.
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PMID:Protein kinase cepsilon has the potential to advance the recurrence of human prostate cancer. 1195 6

Caveolin-1, androgen receptor, c-Myc, and protein kinase Cepsilon (PKCepsilon) proteins are overrepresented in most advanced prostate cancer tumors. Previously, we demonstrated that PKCepsilon has the capacity to enhance the expression of both caveolin-1 and c-Myc in cultured prostate cancer cells and is sufficient to induce the growth of androgen-independent tumors. In this study, we have uncovered further evidence of a functional interplay among these proteins in the CWR22 model of human prostate cancer. The results demonstrated that PKCepsilon expression was naturally up-regulated in recurrent CWR22 tumors and that this oncoprotein was required to sustain the androgen-independent proliferation of CWR-R1 cells in culture. Gene transfer experiments demonstrated that PKCepsilon had the potential to augment the expression and secretion of a biologically active caveolin-1 protein that supports the growth of the CWR-R1 cell line. Antisense and pharmacological experiments provided additional evidence that the sequential activation of PKCepsilon, mitogen-activated protein kinases, c-Myc, and androgen receptor signaling drove the downstream expression of caveolin-1 in CWR-R1 cells. Finally, we demonstrate that mitogen-activated protein kinases were required downstream of PKCepsilon to derepress the transcriptional elongation of the c-myc gene. Our findings support the hypothesis that PKCepsilon may advance the recurrence of human prostate cancer by promoting the expression of several important downstream effectors of disease progression.
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PMID:Regulation of caveolin-1 expression and secretion by a protein kinase cepsilon signaling pathway in human prostate cancer cells. 1218 81

Caveolin-1 is a major component of caveolae and plays a regulatory role in several signalling pathways. Caveolin-1 was recently identified as a metastasis-related gene in prostate cancer. The clinical effects of caveolin-1 expression in pancreatic carcinoma, however, remain unknown. In this study, we have investigated the relationship between caveolin-1 expression and the clinicopathologic variables and clinical outcome in 79 patients with pancreatic adenocarcinoma undergoing surgical resection. Caveolin-1 expression was determined by immunohistochemistry, using a polyclonal anti-caveolin-1 antibody. Patients were divided into two groups based on the extent of caveolin-1 expression: a negative expression group (immunoreactivity in less than 50% of cells) and a positive expression group. Positive caveolin-1 immunostaining was detected in 32 cases (40.5% of total), while non-neoplastic ductal epithelium showed little or no staining. Positive caveolin-1 expression was correlated with tumour diameter (P=0.0079), histopathologic grade (P=0.0272) and poor prognosis (P=0.0008). Upon multivariate analysis with Cox's proportional hazards model, positive caveolin-1 expression was shown to be an independent negative predictor for survival (P=0.0358). These results suggest that caveolin-1 overexpression is associated with tumour progression, thereby indicating a poor prognosis for certain patients undergoing surgical resection for pancreatic carcinoma.
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PMID:Impact of caveolin-1 expression on prognosis of pancreatic ductal adenocarcinoma. 1240 54

Adenoviral vector delivery of the Herpes simplex virus thymidine kinase (HSV-tk) gene in combination with the prodrug ganciclovir (GCV) has been tested in phase I clinical trials for prostate cancer and found to exhibit a satisfactory toxicity profile. We have developed additional adenoviral vectors with differing promoters to optimize the expression profile and in the present study evaluate the potential systemic toxicity of these vectors. Four recombinant adenoviral vectors that express the HSV-tk gene were generated using three different promoters: CMV (leftward orientation); RSV (both rightward and leftward orientation); and the mouse caveolin-1 (cav-1) promoter (leftward orientation). Efficacy was determined in vitro by cytotoxicity assays in a mouse prostate cancer cell line, RM-9, and in vivo by treating orthotopic tumors. Potential toxicity was evaluated from liver histology and apoptotic cell counts and enzyme levels in the serum following intravenous adenoviral vector injection. Although there were differences in HSV-tk expression at the protein level among the four vectors there were no significant differences in in-vitro cytotoxicity studies with GCV or in vivo in tumor growth suppression of an orthotopic mouse prostate cancer model in GCV treated mice. Intravenous delivery of high doses of all adenoviral vectors lead to abnormalities in liver function as measured by specific serum markers and histological evaluation of liver tissue and increased levels of apoptosis in the liver. These abnormalities were most prevalent with the vector containing the CMV promoter and the rightward oriented RSV promoter. They were least prevalent in the vector regulated by the cav-1 promoter. Upregulation of specific chemokines, MIP-2 and MIP-1beta was correlated with apoptotic counts. Our results demonstrate that comprehensive toxicological analysis of adenoviral vectors provides internally consistent information that can differentiate vectors with comparable efficacy based on toxicity. In these studies vectors with the cav-1 promoter-driven and leftward RSV-driven HSV-tk gene demonstrated minimal toxicities with cytotoxic effectiveness comparable to more toxic vectors. Our studies further suggest that promoter selection can influence the toxic effects of an adenoviral gene therapy vector.
Prostate Cancer Prostatic Dis 2002
PMID:Gene therapy for prostate cancer: toxicological profile of four HSV-tk transducing adenoviral vectors regulated by different promoters. 1262 18

Caveolin-1 and -2 are the two major coat proteins found in plasma membrane caveolae of most of cell types. Here, by using adenoviral transduction of either caveolin-1 or caveolin-2 or both isoforms into cells lacking both caveolins, we demonstrate that caveolin-2 positively regulates caveolin-1-dependent caveolae formation. More importantly, we show that caveolin-2 is phosphorylated in vivo at two serine residues and that the phosphorylation of caveolin-2 is necessary for its actions as a positive regulator of caveolin-1 during organelle biogenesis in prostate cancer cells. Mutation of the primary phosphorylation sites on caveolin-2, serine 23 and 36, reduces the number of plasmalemma-attached caveolae and increases the accumulation of noncoated vesicles, but does not affect trafficking of caveolin-2, interaction with caveolin-1 or its biophysical properties. Thus, the phosphorylation of caveolin-2 is a novel mechanism to regulate the dynamics of caveolae assembly.
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PMID:The phosphorylation of caveolin-2 on serines 23 and 36 modulates caveolin-1-dependent caveolae formation. 1274 74

Metastasis represents the ultimate target in cancer therapy as this complex biological process is the direct cause of mortality for a variety of human malignancies. The current high level of mortality from prostate cancer results in large part from the inexorable growth of overt or occult metastasis present at the time of diagnosis. Currently, there are no curative therapies for metastatic prostate cancer. To better understand the metastatic phenotype in prostate cancer, we developed a strategy to identify mRNAs that are expressed differentially in cell lines derived from primary versus metastatic mouse prostate cancer using differential display-PCR. In using this system a number of metastasis-related sequences were identified including a cDNA that encodes caveolin-1. Caveolin-1 was found to be overexpressed not only in metastatic mouse prostate cancer, but also in human metastatic disease. Recent studies have indicated that suppression of caveolin-1 expression induces androgen sensitivity in high caveolin-1, androgen-insensitive mouse prostate cancer cells derived from metastases. Conversely, overexpression of caveolin-1 leads to androgen insensitivity in low caveolin, androgen-sensitive mouse prostate cancer cells. Caveolin-1, therefore, is both a metastasis-related gene as well as a candidate androgen resistance gene for prostate cancer in man. Interestingly, recent studies also point to a potential role for caveolin-1 in the resistance of various malignancies to multiple antineoplastic agents. The linkage of caveolin-1 expression with the androgen-resistant phenotype in prostate cancer and the multidrug resistance phenotype in various solid tumors establishes a novel paradigm for understanding these clinically important and now potentially related processes in malignant progression.
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PMID:Caveolin-1, a metastasis-related gene that promotes cell survival in prostate cancer. 1463 73

Previously it has been reported that caveolin-1 (cav-1) has antiapoptotic activities in prostate cancer cells and functions downstream of androgenic stimulation. In this study, we demonstrate that cav-1 overexpression significantly reduced thapsigargin (Tg)-stimulated apoptosis. Examination of the phosphatidylinositol 3-kinase (PI3-K)/Akt signaling cascade revealed higher activities of PDK1 and Akt but not PI3-K in cav-1-stimulated cells compared to control cells. We subsequently found that cav-1 interacts with and inhibits serine/threonine protein phosphatases PP1 and PP2A through scaffolding domain binding site interactions. Deletion of the cav-1 scaffolding domain significantly reduces phosphorylated Akt and cell viability compared with wild-type cav-1. Analysis of potential substrates for PP1 and PP2A revealed that cav-1-mediated inhibition of PP1 and PP2A leads to increased PDK1, Akt, and ERK1/2 activities. We demonstrate that increased Akt activities are largely responsible for cav-1-mediated cell survival using dominant-negative Akt mutants and specific inhibitors to MEK1/MEK and show that cav-1 increases the half-life of phosphorylated PDK1 and Akt after inhibition of PI3-K by LY294002. We further demonstrate that cav-1-stimulated Akt activities lead to increased phosphorylation of multiple Akt substrates, including GSK3, FKHR, and MDM2. In addition, overexpression of cav-1 significantly increases translocation of phosphorylated androgen receptor to nucleus. Our studies therefore reveal a novel mechanism of Akt activation in prostate cancer and potentially other malignancies.
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PMID:Caveolin-1 maintains activated Akt in prostate cancer cells through scaffolding domain binding site interactions with and inhibition of serine/threonine protein phosphatases PP1 and PP2A. 1464 48

Gene methylation is an important molecular event in prostate carcinogenesis that may have diagnostic and prognostic significance. We evaluated the methylation status of eight genes implicated in prostate carcinogenesis. DNA was extracted from archived paraffin-embedded tumor blocks from 90 prostate cancer patients. Gene methylation status of eight genes (GSTP1, RASSF1A, RARbeta2, CD44, EDNRB, E-cadherin, Annexin-2, and Caveolin-1) was determined using real-time methylation-sensitive PCR techniques. Differences in gene methylation among race, tumor grade and disease stage were evaluated by chi-square test. Of the eight genes, GSTP1, RASSF1A, and RARbeta2 methylation was highly prevalent across tumors (>60% for all three genes) whereas CD44, E-cadherin and EDNRB methylation was less prevalent (33, 24 and 29%, respectively). Annexin-2 and Caveolin-1 were not methylated in any of the tumors examined. Methylation of RARbeta2, CD44 and E-cadherin was correlated with tumor grade but not stage. Interestingly, methylation of EDNRB, a gene involved in angiogenesis, was correlated with stage of disease but not tumor grade. With the possible exception of CD44, we did not observe differences in gene methylation between racial categories for the genes under study. In summary, our data suggest that evaluation of the methylation of a panel of genes may have diagnostic and prognostic utility in prostate cancer.
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PMID:A survey of gene-specific methylation in human prostate cancer among black and white men. 1503 50


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