Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

It has been suggested that the helix-loop-helix protein Id-1 plays an important role in tumourigenesis in certain types of human cancer. Previously, we reported that Id-1 was up-regulated during sex hormone-induced prostate carcinogenesis in a Noble rat model (Ouyang et al. (2001) Carcinogenesis, 22, 965-973). In the present study, we investigated the direct effect of Id-1 expression on human prostate cancer cell proliferation by transfecting an Id-1 expression vector into a prostate cancer cell line LNCaP. Ten stable transfectant clones were isolated and the ectopic Id-1 expression resulted in both increased DNA synthesis rate and the percentage of S phase cells. To study the possible mechanisms involved in the Id-1 induced prostate cancer cell growth, we examined the expression of several factors responsible for G(1) to S phase progression. We found that Id-1 expression induced phosphorylation of RB and down-regulation of p16(INK4a) but not p21(Waf1)or p27(Kip1). Our results indicate that the Id-1 induced inactivation of p16(INK4a)/pRB pathway may be responsible for the increased cell proliferation in prostate cancer cells. Given the fact that both Id-1 over-expression and inactivation of p16(INK4a)/pRB are common events in prostate cancer, our results provide a possible mechanism on the molecular basis of prostate carcinogenesis.
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PMID:Id-1 stimulates serum independent prostate cancer cell proliferation through inactivation of p16(INK4a)/pRB pathway. 1201 43

The helix-loop-helix protein Id-1 has been suggested to play a positive role in cell proliferation and tumorigenesis of many types of human cancers. However, little is known about the molecular mechanism involved in the function of Id-1. In this study, using four stable Id-1 transfectant clones, we investigated the involvement of MAPK signaling pathway in the Id-1 induced serum independent prostate cancer cell growth. Our results demonstrated that both transient and stable ectopic Id-1 expression in prostate cancer LNCaP cells led to activation of the Raf/MEK1/2 signaling pathway. In addition, inhibition of MEK1/2 phosphorylation by one of its inhibitors, PD098059, resulted in the decreased cell cycle S phase fraction and cell growth rate, suggesting that activation of MAPK signaling pathway is essential for Id-1 induced prostate cancer cell proliferation. Furthermore, treatment with antisense oligonucleotide complementary to Id-1 mRNA in PC-3 and DU145 cells resulted in a decreased Id-1 expression which was accompanied by decreased Egr-1 protein. Our results suggest for the first time that the function of Id-1 is associated with MAPK signaling pathway activation and indicate a possible novel mechanism in which Id-1 regulates prostate cancer cell growth and tumorigenesis.
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PMID:Activation of MAPK signaling pathway is essential for Id-1 induced serum independent prostate cancer cell growth. 1246 69

The failure of prostate cancer treatment is largely due to the development of androgen independence, since the androgen depletion therapy remains the front-line option for this cancer. Previously, we reported that over-expression of the helix-loop-helix protein Id-1 was associated with progression of prostate cancer and ectopic expression of Id-1 induced serum-independent proliferation in prostate cancer cells. In the present study, we investigated if exogenous Id-1 expression in the androgen sensitive LNCaP cells had any effect on androgen-dependent cell growth and studied the molecular mechanisms involved. Using stable Id-1 transfectants, we found that expression of Id-1 was able to reduce androgen-stimulated growth and S phase fraction of the cell cycle in LNCaP cells, indicating that Id-1 may be involved in the development of androgen independence in these cells. The Id-1-induced androgen-independent prostate cancer cell growth was correlated with up-regulation of EGF-R (epidermal growth factor-receptor) and PSA (prostate specific antigen) expression, as confirmed by western blotting analysis and luciferase assays. In contrast, down-regulation of Id-1 in androgen-independent DU145 cells by its antisense oligonucleotides resulted in suppression of EGF-R expression at both transcriptional and protein levels. In addition, the results from immunohistochemistry study showed that Id-1 expression was significantly elevated in hormone refractory prostate cancer tissues when compared with the hormone-dependent tumours. Our results suggest that up-regulation of Id-1 in prostate cancer cells may be one of the mechanisms responsible for developing androgen independence and this process may be regulated through induction of EGF-R expression. Inactivation of Id-1 may provide a potential therapeutic strategy leading to inhibition of androgen-independent prostate cancer cell growth.
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PMID:Id-1 expression induces androgen-independent prostate cancer cell growth through activation of epidermal growth factor receptor (EGF-R). 1468 27

Overexpression of the helix-loop-helix protein Id-1 has been reported in over 20 types of cancer. While a number of factors have been demonstrated to regulate Id-1 gene transcription, little is known about the mechanisms responsible for its degradation. In this study, we have demonstrated that Id-1 protein stability was regulated by TNFalpha in prostate cancer cells. We found that exposure of prostate cancer cell lines, DU145 and PC-3, to TNFalpha resulted in a rapid and significant downregulation of the Id-1 protein level. The fact that neither the Id-1 promoter activity nor the Id-1 mRNA level was affected by the TNFalpha treatment suggested that the decrease in Id-1 protein was not due to the suppression of gene transcription. In addition, the half-life of the Id-1 protein was decreased in both cell lines in the presence of TNFalpha, and the addition of an ubiquitin/proteasome inhibitor (MG-132) prior to the TNFalpha treatment completely blocked the effect of the TNFalpha-induced Id-1 protein degradation. Furthermore, introduction of a Flag-tag sequence into the N-terminus region of the Id-1 protein, which has been shown to stabilize the protein, was able to protect the Id-1 protein from TNFalpha-induced degradation. These results suggest that TNFalpha downregulated Id-1 through activation of the ubiquitin/proteasome degradation pathway in prostate cancer cells. Interestingly, in both DU145 and PC-3 cells, the decrease of Id-1 protein was associated with the activation of apoptotic pathway, as evidenced by the increased expression of cleaved PARP and caspase 3. In addition, TNFalpha failed to downregulate Id-1 in a sub-line of LNCaP cells that was resistant to TNFalpha-induced apoptosis. These results further suggest that the downregulation of Id-1 may facilitate TNFalpha-induced apoptosis in prostate cancer cells. In conclusion, our findings indicate that Id-1 protein may be regulated by TNFalpha through the ubiquitin/proteasome degradation pathway and the stability of the Id-1 protein appears to correlate with the sensitivity of TNFalpha-induced apoptosis.
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PMID:Proteasome mediated degradation of Id-1 is associated with TNFalpha-induced apoptosis in prostate cancer cells. 1612 20

A major hurdle in understanding the role of androgens is the heterogeneity of androgen receptor (AR) expression in the prostate. Because the majority of prostate cancer arises from the AR-positive secretory luminal epithelial cells, identifying the androgen-mediated pathways in the prostate epithelium is of great significance to understanding their role in prostate pathogenesis. To meet this objective, the current study was designed to identify immediate-early genes expressed in response to the synthetic androgen R1881 in cultured rat ventral prostate epithelial cells. Rat ventral prostate epithelial cells, purified from 20-d-old rats, were cultured, and the presence of AR and the response to androgen were established. The cells were then treated with R1881 for 2 and 12 h to capture immediate-early genes in an Affymetrix-based gene chip platform. A total of 66 nonredundant genes were identified that were responsive to R1881. The functional androgen response elements were identified in the proximal promoter to determine possible molecular mechanism. Cluster analysis identified five distinct signatures of R1881-induced genes. Pathway analysis suggested that R1881 primarily influences cell proliferation/differentiation and inflammatory/immune response pathways. Androgens appear to regulate cell renewal by regulating differentiation, cell proliferation, and apoptosis. Two mutually exclusive inflammatory response pathways were observed. The interferon pathway was up-regulated, and the ILs were down-regulated. The data identified novel androgen-regulated genes (e.g. Id1, Id3, IL-6, IGF-binding protein-2 and -3, and JunB). The loss of androgen regulation of these genes can have important consequences for cellular transformation and transition to androgen-independent growth and survival.
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PMID:Androgens regulate the immune/inflammatory response and cell survival pathways in rat ventral prostate epithelial cells. 1619 7

Id proteins are a class of dominant-negative antagonists of helix-loop-helix transcription factors and have been shown to control differentiation of a variety of cell types in diverse organisms. Although the importance of Id1 in tumor endothelial cells is well established, the expression and role of the Id1 protein in human cancer cells is controversial. To explore this issue, we developed and characterized a highly specific rabbit monoclonal antibody against Id1 to assess its expression in human breast, prostate, and bladder malignancies. Our results show that in usual types of human mammary carcinomas, the Id1 protein is expressed exclusively in the endothelium. Interestingly, we detected nuclear expression of the Id1 protein in the tumor cells in 10 of 45 cases of poorly differentiated and highly aggressive carcinoma with metaplastic morphology. Similarly, only 1 of 30 prostate cancer samples showed Id1-positive tumor cells, whereas in almost all, endothelial cells showed high Id1 expression. Intriguingly, whereas normal prostate glands do not show any Id1 protein expression, basal layer cells of benign prostate glands in proximity to tumors expressed high levels of the Id1 protein. In contrast to the lack of Id1 expression in the usual types of mammary and prostate cancers, the majority of transitional cell bladder tumors showed Id1 protein expression in both tumor and endothelial cells. These results suggest that further refinement of Id1 expression patterns in a variety of tumor types will be necessary to identify and study the functional roles played by Id1 in human neoplastic processes.
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PMID:Reassessment of id1 protein expression in human mammary, prostate, and bladder cancers using a monospecific rabbit monoclonal anti-id1 antibody. 1710 23

A dynamic interplay between prostate cancer cells and reactive bone stroma modulates growth of metastases within bone. We used microarray analysis to screen for changes in gene expression in bone marrow stromal cells cocultured with prostate cancer cells and found reduced expression of endoglin, a transmembrane glycoprotein that functions as an auxiliary coreceptor for members of the transforming growth factor beta (TGF-beta) family of cytokines. The downstream TGF-beta/bone morphogenetic protein signaling pathway including Smad1 and Smad2/3 also was attenuated, as was Smad-dependent gene transcription. Smad1/5/8-dependent inhibitor of DNA binding 1 expression and Smad2/3-dependent plasminogen activator inhibitor I expression both were decreased and were accompanied by decreased cell proliferation. Small interfering RNA-mediated knockdown of endoglin in HS-5 cells verified that the effects on signaling were a direct result of the attenuation of endoglin. These data illustrate that endoglin acts as a positive regulator of both activin receptor-like kinase 1-induced Smad1/5/8 activation and activin receptor-like kinase 5-induced Smad2/3 activation in bone marrow stromal cells. In addition, the data illustrate that one early event of metastasis upon the arrival of prostate cancer cells into the bone stroma is attenuated endoglin expression in the stromal cells, which subsequently alters Smad signaling and cell proliferation. We hypothesize that coculture of bone marrow stromal cells with prostate cancer cells alters TGF-beta signaling in the stromal cells, ultimately facilitating growth of the cancer cells in the bone compartment. Collectively, these studies suggest that prostate cancer cells modulate TGF-beta responsiveness of bone marrow stroma as one means of facilitating their own growth in bone.
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PMID:Coculture with prostate cancer cells alters endoglin expression and attenuates transforming growth factor-beta signaling in reactive bone marrow stromal cells. 1757 18

Tocotrienol-rich fraction (TRF) has demonstrated antiproliferative effect on prostate cancer (PCa) cells. To elucidate this anticancer property in PCa cells, this study aimed, first, to identify the most potent isomer for eliminating PCa cells; and second, to decipher the molecular pathway responsible for its activity. Results showed that the inhibitory effect of gamma-tocotrienol was most potent, which resulted in induction of apoptosis as evidenced by activation of pro-caspases and the presence of sub-G(1) cell population. Examination of the pro-survival genes revealed that the gamma-tocotrienol-induced cell death was associated with suppression of NF-kappaB, EGF-R and Id family proteins (Id1 and Id3). Meanwhile, gamma-tocotrienol treatment also resulted in the induction of JNK-signalling pathway and inhibition of JNK activity by a specific inhibitor (SP600125) was able to partially block the effect of gamma-tocotrienol. Interestingly, gamma-tocotrienol treatment led to suppression of mesenchymal markers and the restoration of E-cadherin and gamma-catenin expression, which was associated with suppression of cell invasion capability. Furthermore, a synergistic effect was observed when cells were co-treated with gamma-tocotrienol and Docetaxel. Our results suggested that the antiproliferative effect of gamma-tocotrienol act through multiple-signalling pathways, and demonstrated for the first time the anti-invasion and chemosensitisation effect of gamma-tocotrienol against PCa cells.
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PMID:Gamma-tocotrienol suppresses prostate cancer cell proliferation and invasion through multiple-signalling pathways. 1900 71

Id1 (inhibitor of differentiation 1) is a member of the bHLH protein family. Consistent with its role in promoting proliferation and inhibiting differentiation, Id1 expression is low or negligible in normal prostate epithelial cells but is high in prostate cancer. Ectopic expression of Id1 in normal prostate epithelial cells could therefore provide a model for understanding early events involved in initiation of prostate cancer. Over-expression of Id1 immortalized but did not transform ventral prostate epithelial cells (Id1-RPE). Immortalization was associated with decreased Cdkn2a, Cdkn1a, androgen receptor and increased Tert expression. Gene expression profiling over successive doublings was used to identify transcriptomic changes involved during immortalization (Tieg, Jun, alpha actin, Klf10, Id2) and in maintaining the immortalized phenotype (Igfbp3, Igfbp5, Mmp2, Tgfb3). Network analysis indicated that Id1 promotes cancer/tumor morphology, cell cycle and epithelial to mesenchymal transition by influencing AP1, tnf, tgfbeta, PdgfBB and estradiol pathways. During immortalization, the expression of majority of differentially expressed genes reduced over progressive doublings suggesting a decline in transcriptional regulatory mechanisms. The associated molecular/gene expression profile of Id1-RPE cells provides an opportunity to understand the molecular pathways associated with prostate epithelial cell survival and proliferation.
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PMID:Inhibitor of differentiation 1 (ID1) promotes cell survival and proliferation of prostate epithelial cells. 2018 95

gamma-Tocotrienol (gammaT3) is known to selectively kill prostate cancer (PCa) cells and to sensitize the cells to docetaxel (DTX)-induced apoptosis. In the present study, the pharmacokinetics of gammaT3 and the in vivo cytotoxic response of androgen-independent prostate cancer (AIPCa) tumor following gammaT3 treatment were investigated. Here, we investigated these antitumor effects for PCa tumors in vivo. The pharmacokinetic and tissue distribution of gammaT3 after exogenous gammaT3 supplementation were examined. Meanwhile, the response of the tumor to gammaT3 alone or in combination with DTX were studied by real-time in vivo bioluminescent imaging and by examination of biomarkers associated with cell proliferation and apoptosis. After intraperitoneal injection, gammaT3 rapidly disappeared from the serum and was selectively deposited in the AIPCa tumor cells. Administration of gammaT3 alone for 2 weeks resulted in a significant shrinkage of the AIPCa tumors. Meanwhile, further inhibition of the AIPCa tumor growth was achieved by combined treatment of gammaT3 and DTX (p < 0.002). The in vivo cytotoxic antitumor effects induced by gammaT3 seem to be associated with a decrease in expression of cell proliferation markers (proliferating cell nuclear antigen, Ki-67 and Id1) and an increase in the rate of cancer cell apoptosis [cleaved caspase 3 and poly(ADP-ribose) polymerase]. Additionally, the combined agents may be more effective at suppressing the invasiveness of AIPCa. Overall, our results indicate that gammaT3, either alone or in combination with DTX, may provide a treatment strategy that can improve therapeutic efficacy against AIPCa while reducing the toxicity often seen in patients treated with DTX.
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PMID:In vivo evidence of gamma-tocotrienol as a chemosensitizer in the treatment of hormone-refractory prostate cancer. 2037 35


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