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)

Hyperthermia is being utilized individually and in conjunction with other therapies in treating malignant and benign tumors, though few studies have examined cellular effects of elevated temperatures in the prostate model. Highly conserved proteins of the 70 kDa heat shock protein family (HSP 70) are produced in response to environmental stresses, including heat, and are found in all organisms. HSPs are an indicator of cell damage, are associated with thermotolerance, and provide cells with transient resistance to subsequent thermal challenges. Transient thermotolerance is important in the determination of temperature, duration, and sequencing for treatments. This preliminary study analyzes the HSP 70 response of the Dunning R3327 adenocarcinoma model to a single 50 degrees C 1 hr treatment. Elevated HSP levels were found between 10 and 16 hr, returning to baseline by 24 hr. As some fractions of the cells are able to produce HSP 70 following treatment, the data suggest that currently utilized clinical temperatures (42-46 degrees C) administered for 1 hr are inadequate. HSP levels in response to hyperthermia, radiation, and chemotherapy may be useful in finding optimal treatment regimens for prostate cancer.
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PMID:Heat shock protein response in a prostate tumor model to interstitial thermotherapy: implications for clinical treatment. 823 68

We have studied the response to oestrogen and expression of oestrogen receptors in responsive LNCaP and androgen non-responsive PC3 human prostate cancer cell lines. Growth of LNCaP cells is significantly stimulated by physiological concentrations of oestradiol; this growth increase appears to be comparable to that induced by either testosterone or dihydrotestosterone. In contrast, oestradiol significantly inhibits the proliferation of PC3 cells. We also present novel evidence for functional oestrogen binding in LNCaP cells. This evidence was first obtained by means of radioligand binding assays and was further corroborated using: (a) immunocytochemical analysis of oestrogen and progesterone receptors; (b) reverse transcriptase polymerase chain reaction of oestrogen receptor mRNAs; and (c) immunofluorescence of the 27 kDa heat shock protein (Hsp27), which has been reported to be a marker of functional oestrogen receptors. There appeared to be significantly and consistently lower levels of oestrogen receptor expressed in PC3 cells than in LNCaP cells. The observation that oestradiol-induced growth of LNCaP cells is completely reversed by the pure anti-oestrogen ICI 182,780 clearly implies that the biological response of these cells to oestradiol is mediated mainly via its own receptor. On the other hand, use of a neutralizing antibody against transforming growth factor (TGF)-beta 1 results in a remarkable increase in the growth of PC3 cells; this effect is almost completely abolished after the addition of oestradiol. This suggests that the oestradiol-induced growth inhibition may be mediated by TGF-beta 1. These results suggest that the current model for hormone-dependence of human prostatic carcinoma should be revised. This is of special concern, because recent data indicate that prostate cancer has become the most prevalent cancer and the second principal cause of cancer death in western countries.
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PMID:Human prostate cancer: a direct role for oestrogens. 858 3

BAG-1 is a regulator of heat shock protein (Hsp) 70/Hsc70 family proteins that interacts with steroid hormone receptors. The recently identified BAG-1 long (BAG-1L) protein, an isoform of BAG-1 that arises from translation initiation at a noncanonical CUG codon, was co-immunoprecipitated with androgen receptors (AR) from LNCaP prostate cancer cells and other cell lysates, whereas the shorter originally identified BAG-1 and BAG-1M (RAP 46) proteins were not. BAG-1L, but not BAG-1 or BAG-1M (RAP46), also markedly enhanced the ability of AR to transactivate reporter gene plasmids containing an androgen response element (ARE) in PC3 prostate cancer and other cell lines. A C-terminal region deletion mutant of BAG-1L failed to co-immunoprecipitate with AR and functioned as a trans-dominant inhibitor of BAG-1L, impairing AR-induced transactivation of ARE-containing reporter plasmids. In addition, BAG-1L significantly reduced the concentrations of 5alpha-dihydrotestosterone (DHT) required for AR activity but did not induce ligand-independent transactivation. BAG-1L also markedly improved the ability of AR to transactivate reporter genes when cells were cultured with DHT in combination with the anti-androgen cyproterone acetate. The effects of BAG-1L on AR could not be explained by detectable alterations in the DHT-induced translocation of AR from cytosol to nucleus, nor by BAG-1L-induced increases in the amounts of AR protein. These findings implicate BAG-1L in the regulation of AR function and may have relevance to mechanisms of prostate cancer resistance to hormone-ablative and anti-androgen therapy.
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PMID:BAG-1L protein enhances androgen receptor function. 956 86

Tumor-derived purified heat shock protein (HSP), gp96, has tumor protective effect in a number of experimental cancers that include fibrosarcoma, hepatoma, and spindle cell carcinoma. The rationale for using gp96 as a vaccinating agent stems from the discovery that HSPs, including gp96, chaperone antigenic peptides for eventual recognition and elicitation of an immune response. The immune response generated by the HSP-peptide complex is specific to the tumor from which they are derived. The long-term objective of our studies is to develop a vaccine for primary and metastatic prostate cancer using tumor-derived HSPs. In the present study, we report our results on the tumor protective effect of irradiated Dunning G cells, or purified preparations of g96-peptide complexes as a tumor vaccine. Tumor incidence, latency, and tumor growth were the end points of measurement. Tumor bearing Copenhagen rats, made free of disease by surgical resection of the tumors resisted a fresh challenge of live Dunning G tumor cells. Vaccination with irradiated whole cells failed to elicit any resistance to tumor growth. Vaccination with Dunning G derived purified gp96-peptide complexes delayed both incidence and growth of Dunning G induced tumors. Inhibition of tumor growth was observed when gp96 was administered after tumor induction. Our data suggests that tumor derived gp96-peptide complexes can be used as an effective prophylactic and therapeutic agent even in poorly immunogenic cancer such as prostate cancer. Further investigations will determine specificity of action and define the immunological determinants and experimental conditions for its optimal activity.
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PMID:Preventive and therapeutic effect of tumor derived heat shock protein, gp96, in an experimental prostate cancer model. 1042 72

Androgen deprivation induces substantial changes in the phenotype of prostate cancer that are accompanied by alterations in protein expression. Immunohistochemical studies allow precise cellular localization of such expression, thereby providing an understanding of the biochemical alterations caused by therapy. Expression of proteins may be increased (e.g., multiple growth factors, heat shock protein), decreased (e.g., microvessel density, proliferation markers, certain integrins), or remain unchanged (e.g., prostate specific antigen, prostatic acid phosphatase, prostate-specific membrane antigen, and other secretory proteins). Variations in immunoreactivity may be of prognostic value in some patients. This report summarizes the existing literature regarding changes in tissue expression of proteins, as determined by immunohistochemistry, and the clinical implications of these changes.
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PMID:Immunohistochemical changes in prostate cancer after androgen deprivation therapy. 1106 63

Functional analysis of androgen receptor (AR) gene mutations isolated from prostate cancer has led to the identification of residues that play important roles in the structure and function of the receptor. Here we report the characteristics of a novel AR mutation A748T located in helix 5 of the ligand-binding domain, which was identified in metastatic prostate cancer. Despite a normal hormone-binding affinity, A748T causes hormone concentration-dependent defects in nuclear accumulation and transcriptional activation. Moreover, when equivalent amounts of DNA are transfected, the mutant is expressed at much lower levels than the wild-type AR (ARWT). Treatment with geldanamycin to disrupt receptor-heat shock protein complexes rapidly decreases the levels of ARWT but not A748T, suggesting that the lower expression and rapid degradation rate of A748T is due to weaker interactions with heat shock proteins. Further analysis revealed that hormone dissociates from A748T five times faster than from ARWT. Loss of the ability to form stable amino/carboxyl-terminal interactions causes accelerated dissociation rates in some AR mutants. However, A748T exhibits normal amino/carboxyl-terminal interactions at high hormone concentrations, suggesting that the mutation alters interactions with ligand. Consistent with this conclusion, our structural model predicts that A748T disrupts crucial contact points with ligand, thereby altering the conformation of the ligand-binding domain.
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PMID:A novel androgen receptor mutant, A748T, exhibits hormone concentration-dependent defects in nuclear accumulation and activity despite normal hormone-binding affinity. 1245 91

Rapamycin inhibits the FK506-binding protein 12 (FKBP12)/mammalian target of rapamycin (mTOR) complex and causes cell cycle arrest in G1. The precise mechanism of growth inhibition by rapamycin is only partly understood. Rapamycin led to growth inhibition in the human prostate cancer cell lines LNCaP and PC3 cells after 72 h, ID50: 93 and 50 nM, respectively. Filter cDNA array analysis showed down-regulation by more than 0.75x by rapamycin in PC3 cells and LNCaP cells of the following genes: follistatin, eukaryotic initiation factor-4E (eIF4E), glucose-6-phosphate dehydrogenase (GAPDH), lactate dehydrogenase (LDH)-A, ATP synthase, heat shock protein (HSP)-1. Upregulation by more than 1.5x was found for: bone morphogenetic protein (BMP)-4, FKBP12, carcinoma embryonic antigen (CEA) precursor, eukaryotic initiation factor (eIF)-3 p36 subunit, latent transforming growth factor (TGF) beta binding protein (LTBP)1. Rapamycin induced BMP4 and reduced follistatin expression in PC3 cells. This resulted in a dose-dependent nuclear expression of Smad4 and activated the SBE4 Smad-reporter, indicating activation of TGFbeta/BMP signaling. Combining rapamycin with PI3K inhibition (LY294002) increased growth inhibition. These findings illustrate that Smad signaling plays a role in the anticancer effects of rapamycin and show that combination with PI3K inhibition improves growth inhibition.
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PMID:Rapamycin induces Smad activity in prostate cancer cell lines. 1259 18

H11, the eukaryotic homologue of a herpes simplex virus protein, has the crystallin motif of heat shock proteins (Hsp), but it differs from canonical family members in that mRNA and protein levels were reduced in various tumor tissues and cell lines (viz. melanoma, prostate cancer and sarcoma) relative to their normal counterparts. In these cells, expression was not restored by heat shock, but rather by the demethylating agent 5-aza-2'-deoxycytidine (Aza-C). Forced H11 expression by Aza-C treatment, transient transfection with H11 expression vectors, or retrovirus-mediated delivery of H11 under the control of a tetracycline-sensitive promoter triggered apoptosis. This is evidenced by a significant (p < 0.001) increase in the percentage of cells positive for terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) and for activation of caspase-3 and p38MAPK and by the co-localization of TUNEL+ nuclei with increased H11 levels. Apoptosis was partially inhibited by the pancaspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone or the p38MAPK inhibitor SB203580. It was abrogated by co-treatment with both inhibitors, suggesting that H11-triggered apoptosis is both caspase- and p38MAPK-dependent. A single site mutant (H11-W51C) had cytoprotective activity related to MEK/ERK activation, and it blocked H11-induced apoptosis in co-transfected and Aza-C-treated cells, indicating that it is a dominant negative mutant. This is the first report of a heat shock protein with proapoptotic activity.
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PMID:Forced expression of the H11 heat shock protein can be regulated by DNA methylation and trigger apoptosis in human cells. 1283 17

The major heat shock protein Hsp72 is expressed at high levels in various types of cancer. Here we attempt to clarify the role of Hsp72 in prostate cancer cells by studying the effects of specific downregulation of this protein using siRNA and antisense RNA approaches. Contrary to previous reports, specific depletion of Hsp72 did not reduce viability of the prostate carcinoma cell lines PC-3 and DU-145. However, even short-term downregulation of Hsp72 in these cells made them more sensitive to hyperthermia, inhibitors of proteasome and Hsp90, and tumor necrosis factor. Interestingly, prolonged downregulation of Hsp72 in PC-3 cells over 3 weeks aggravated these effects, as well as enhanced the sensitivity of cells to oxidative stress, radiation, cis-platinum, vinblastin and taxol. The increased sensitivity to the anticancer agents was due to increased apoptosis, as well as other types of cell death, which resulted in the loss of clonogenic survival. Prolonged downregulation of Hsp72 led to severe suppression of the major survival pathways, ERK and NF-kappaB, which may be responsible for enhanced sensitivity of prostate carcinoma cells to a variety of anticancer treatments, as well as reduction of the cell's capability of forming colonies in soft agar.
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PMID:Increased expression of the major heat shock protein Hsp72 in human prostate carcinoma cells is dispensable for their viability but confers resistance to a variety of anticancer agents. 1573 99

Androgen receptor plays a critical role in the development of primary as well as advanced hormone-refractory prostate cancer. Therefore, ablation of androgen receptor from prostate cancer cells is an interesting concept for developing a new therapy not only for androgen-dependent prostate cancer but also for metastatic hormone-refractory prostate cancer, for which there is no effective treatment available. We report here that LAQ824, a cinnamyl hydroxamatic acid histone deacetylase inhibitor currently in human clinical trials, effectively depleted androgen receptor in prostate cancer cells at nanomolar concentrations. LAQ824 seemed capable of depleting both the mutant and wild-type androgen receptors in either androgen-dependent and androgen-independent prostate cancer cells. Although LAQ824 may exert its effect through multiple mechanisms, several lines of evidence suggest that inactivation of the heat shock protein-90 (Hsp90) molecular chaperone is involved in LAQ824-induced androgen receptor depletion. Besides androgen receptor, LAQ824 reduced the level of Hsp90 client proteins HER-2 (ErbB2), Akt/PKB, and Raf-1 in LNCaP cells. Another Hsp90 inhibitor, 17-allyamino-17-demethoxygeldanamycin (17-AAG), also induced androgen receptor diminution. LAQ824 induced Hsp90 acetylation in LNCaP cells, which resulted in inhibition of its ATP-binding activity, dissociation of Hsp90-androgen receptor complex, and proteasome-mediated degradation of androgen receptor. Consequently, LAQ824 blocked androgen-induced prostate-specific antigen production in LNCaP cells. LAQ824 effectively inhibited cell proliferation and induced apoptosis of these prostate cancer cells. These results reveal that LAQ824 is a potent agent for depletion of androgen receptor and a potential new drug for prostate cancer.
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PMID:Chemical ablation of androgen receptor in prostate cancer cells by the histone deacetylase inhibitor LAQ824. 1617 22


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