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)

The androgen-regulated protein androgen-induced bZIP (AIbZIP) is a bZIP transcription factor that localizes to the membrane of the endoplasmic reticulum (ER). The physiological role of AIbZIP is unknown, but other ER-bound transcription factors such as ATF6 and SREBPs play a crucial role in the regulation of protein processing and lipid synthesis, respectively. In response to alterations in the intracellular milieu, ATF6 and SREBPs are processed to their transcriptionally active forms by regulated intramembrane proteolysis. In humans, AIbZIP mRNA is expressed in several organs including the pancreas, liver, and gonads, but it is especially abundant in prostate epithelial cells. We therefore used LNCaP human prostate cancer cells as a model to identify stimuli that lead to AIbZIP activation and define the transcriptional targets of AIbZIP. In LNCaP cells, AIbZIP was processed to its transcriptionally active form by drugs that deplete ER calcium stores (i.e., A23187 and caffeine), but it was unaffected by an inhibitor of protein glycosylation (tunicamycin). To identify AIbZIP-regulated genes, we generated LNCaP cell lines that conditionally express the processed form of AIbZIP and used Affymetrix microarrays to screen for AIbZIP-regulated transcripts. Selected genes (n = 48) were validated by Northern blot hybridization. The results reveal that the downstream targets of AIbZIP include genes that are implicated in protein processing (e.g., BAG3, DNAJC12, KDELR3). Strikingly, a large number of AIbZIP-regulated transcripts encode proteins that are involved in transcriptional regulation, small molecule transport, signal transduction, and metabolism. These results suggest that AIbZIP plays a novel role in cell homeostasis.
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PMID:Transcriptional profiling of genes that are regulated by the endoplasmic reticulum-bound transcription factor AIbZIP/CREB3L4 in prostate cells. 1771 38

Death receptor 4 (DR4) is a receptor of the antitumor death ligand, TNF-related apoptosis-inducing ligand (TRAIL), and is considered a promising molecular target for cancer therapy. Here, we show a novel regulation of DR4 protein. Tunicamycin treatment, which is an inducer of endoplasmic reticulum (ER)-stress, generated a lower molecular-weight pattern of DR4, but not DR5 protein in prostate cancer DU145 and PC3 cells. Thus, we termed the small form of DR4 protein, DR4-Small (DR4-S) and the large form, DR4-Large (DR4-L). Using DR4 siRNA, we confirmed that DR4-S also stands for DR4 protein. Other ER-stress inducers, brefeldin A and thapsigargin did not generate DR4-S. On the other hand, these ER-stress inducers increased DR5 protein. Tunicamycin induces ER-stress following the inhibition of N-linked glycosylation. Thus, we examined DR4 protein in cell lysates treated with glycosydase. Glycosydase treatments generated DR4-S protein, similar to tunicamycin. These results indicate that tunicamycin regulates DR4 protein size via inhibition of glycosylation.
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PMID:Glycosylation modulates TRAIL-R1/death receptor 4 protein: different regulations of two pro-apoptotic receptors for TRAIL by tunicamycin. 1791 79

Androgen-induced bZIP (AIbZIP/CREB3L4) is a transcription factor of the bZIP family that associates with the membrane of the endoplasmic reticulum (ER). In humans, AIbZIP RNA is most abundant in the prostate gland where the protein is produced in luminal cells of the glandular epithelium. AIbZIP could play an important role in prostate cancer because its expression is up-regulated by androgens in LNCaP prostate cancer cells and the protein is more abundant in cancerous than in non-cancerous prostate cells. We recently added 74 adenocarcinomas and 43 specimens of prostatic intraepithelial neoplasia (PIN) to our survey of AIbZIP expression in prostate tumours. This study showed that AIbZIP is expressed in all grades of adenocarcinoma and that it is more abundant in high-grade PIN and in adenocarcinoma than in normal prostate. The physiological function of AIbZIP remains unknown but its association with the ER and its structural homology to transcription factors such as ATF6 suggest that AIbZIP could be activated by regulated intramembrane proteolysis during the cellular response to ER stress. This review will describe the characteristics of human and mammalian AIbZIP, its relationship to prostate cancer, and our recent efforts to characterize the transcriptional properties and targets of AIbZIP.
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PMID:Androgen-regulated transcription factor AIbZIP in prostate cancer. 1793 19

Cripto is a multifunctional cell surface protein with important roles in vertebrate embryogenesis and the progression of human tumors. While Cripto has been shown to modulate multiple signaling pathways, its binding partners do not appear to fully explain its molecular actions. Therefore, we conducted a screen aimed at identifying novel Cripto-interacting proteins. This screen led to our identification of glucose-regulated protein 78 (GRP78), an endoplasmic reticulum (ER) chaperone that is also expressed at the surfaces of tumor cells. Here we demonstrate that Cripto and GRP78 interact at the cell surfaces of multiple cell lines and that their interaction is independent of prior association within the ER. Interestingly, short hairpin RNA knockdown of endogenous GRP78 resulted in enhanced transforming growth factor beta (TGF-beta) signaling, indicating that like Cripto, GRP78 inhibits this pathway. We further show that when coexpressed, GRP78 and Cripto collaborate to antagonize TGF-beta responses, including Smad phosphorylation and growth inhibition of prostate cancer cells grown under anchorage-dependent or -independent conditions. Finally, we provide evidence that cells coexpressing GRP78 and Cripto grow much more rapidly in soft agar than do cells expressing either protein individually. Together, our results indicate that these proteins bind at the cell surface to enhance tumor growth via the inhibition of TGF-beta signaling.
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PMID:GRP78 and Cripto form a complex at the cell surface and collaborate to inhibit transforming growth factor beta signaling and enhance cell growth. 1799 93

Store-operated Ca2+ channels control homeostasis between extracellular Ca2+ reservoir and intracellular Ca2+ storage and play important roles in apoptosis in a wide variety of cells, including prostate epithelia. Recent studies have shown that the acquired apoptosis-resistant nature of androgen-independent prostate cancer is associated with reduced function of store-operated Ca2+ entry (SOCE). This study investigates the functional interaction between Bax and SOCE in the apoptosis signaling cascade in prostate cancer. Our previous findings show that NRP-154, an androgen-independent prostate cancer cell line, could sustain overexpression of exogenous Bax without undergoing apoptosis. Here we show that sustained overexpression of Bax in NRP-154 cells leads to down-regulation of SOCE and reduced Ca2+ storage inside the endoplasmic reticulum. While reduced SOCE may represent an adaptive mechanism for cell survival, increased levels of Bax in the latent state enhances the sensitivity of NRP-154 cells to TGF-beta and thapsigargin-induced apoptosis. This enhanced apoptosis can be reduced by 2-aminoethoxydiphenyl borate (2-APB), an inhibitor of SOCE, or reversed under conditions where SOCE is only partially activated. Our results demonstrate a functional interaction between Bax and SOCE in apoptosis of prostate cancer, and support the concept that improving this interaction has therapeutic implications for prostate cancer.
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PMID:Overexpression of Bax induces down-regulation of store-operated calcium entry in prostate cancer cells. 1824 59

Granulocyte-macrophage colony-stimulating factor (GM-CSF) holds immunotherapeutic promise in prostate cancer as it activates the host immune system. Increased production of GM-CSF by cancer cells may facilitate host immunosurveillence by the dendritic cells (DC). Here, we studied the effects of kaempferol (K) and quercetin (Q) on the production of GM-CSF in PC-3 cells. Human cytokine antibody array revealed that treatment with K or Q increased GM-CSF release by PC-3 cells. We further observed by ELISA that K and Q in a concentration-dependent manner increased GM-CSF production without affecting its mRNA levels. Inhibitors of vesicular traffic through the endoplasmic reticulum and Golgi-blocked GM-CSF secretory stimulation. A microtubule-stabilizing agent stimulated GM-CSF release, whereas tubulin and actin depolymerizers suppressed K- or Q-stimulated secretion of GM-CSF. Depletion of extracellular or intracellular calcium ion inhibited the GM-CSF secretion upregulated by both K and Q. Furthermore, we showed that K- and Q-stimulated GM-CSF production involves PLC, PKC, and MEK1/2 activation. Treating human DC with the conditioned medium of K- or Q-incubated PC-3 cells increased chemotaxis of DC, which was significantly attenuated when the conditioned medium was incubated with the neutralizing antibody against GM-CSF. Taken together, our results demonstrate that K and Q activate an immune response in the prostate cancer cells by stimulating GM-CSF production, which in turn could result in the recruitment of DCs to the tumor site.
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PMID:Kaempferol and quercetin stimulate granulocyte-macrophage colony-stimulating factor secretion in human prostate cancer cells. 1834 43

Glucocorticoid hormones (GCs) have been widely used for the treatment of prostate cancer because of their inhibitory property against tumour growth. However, their mechanism of action in the prostate has received little attention. Excess GCs can lead to peripheral insulin resistance resulting in hyperglycaemia and hyperinsulinaemia. Insulin plays an important role as a cellular stimulant and high levels are related to low levels of androgens. Our objective has been to describe the effects of insulin resistance induced by dexamethasone treatment on the morphology of rat ventral prostate. Male adult Wistar rats received daily intraperitoneal injections of dexamethasone or saline for five consecutive days after which the rats were killed and the ventral prostate was removed, weighed and prepared for conventional and transmission electron microscopy (TEM). Dexamethasone treatment resulted in atrophy and decreased proliferative activity of prostatic epithelial cells. TEM analysis revealed changes in the epithelium-stroma interface, with some interruptions in the basement membrane. Fibroblasts showed a secretory phenotype with dilated endoplasmic reticulum. Smooth muscle cells exhibited a contractile pattern with 50% atrophy, an irregular membrane and twisted nuclei. Mitochondrial alterations, such as enlarged size and high electron density in the mitochondrial matrix, were also detected in smooth muscle cells. Insulin resistance induced by dexamethasone is thus associated with epithelial atrophy similar to that described for diabetic rats. However, GCs are responsible for morphological changes in the stromal cell population suggesting the activation of fibroblasts and atrophy of the smooth muscle cells.
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PMID:Cellular changes in the prostatic stroma of glucocorticoid-treated rats. 1837 25

Melanoma differentiation-associated gene-7 (mda-7)/interleukin-24 (IL-24) is a cancer-specific, apoptosis-inducing gene with broad-spectrum antitumor activity, making it an ideal candidate for a novel cancer gene therapy. A systemic and sustained antitumor immune response generated at the time of initial molecular-targeted therapy would provide additional clinical benefits in cancer patients, resulting in improved prevention of tumor recurrence. In this study, we explored the therapeutic efficacy of intratumoral delivery of a nonreplicating adenoviral vector encoding mda-7/IL-24 (Ad.mda-7) and a secretable form of endoplasmic reticulum resident chaperone grp170 (Ad.sgrp170), a potent immunostimulatory adjuvant and antigen carrier. Intratumoral administration of Ad.mda-7 in combination with Ad.sgrp170 was more effective in controlling growth of TRAMP-C2 prostate tumor compared with either Ad.mda-7 or Ad.sgrp170 treatment. Generation of systemic antitumor immunity was shown by enhanced protection against subsequent tumor challenge and improved control of distant tumors. The combined treatments enhanced antigen and tumor-specific T-cell response, as indicated by increased IFN-gamma production and cytolytic activity. Antibody depletion suggests that CD8(+) T cells may be involved in the antitumor effect of the dual molecule-targeted therapies. Therefore, introducing immunostimulatory chaperone grp170 in situ strongly promotes the "immunogenic" cell death when delivered to the mda-7/IL-24-induced apoptotic tumor cells, indicating that an improved anticancer efficacy may be achieved by concurrently targeting both tumor and immune compartments. Given multiple undefined antigens present endogenously within prostate cancer, these data provide a rationale for combining sgrp170-based vaccine strategy with mda-7/IL-24-targeted cancer therapy to induce durable systemic immunity.
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PMID:Secretable chaperone Grp170 enhances therapeutic activity of a novel tumor suppressor, mda-7/IL-24. 1848 74

An unbiased cDNA expression phage library derived from bone-marrow endothelial cells was used to identify novel surface adhesion molecules that might participate in metastasis. Herein we report that reticulocalbin 1 (RCN1) is a cell surface-associated protein on both endothelial (EC) and prostate cancer (PCa) cell lines. RCN1 is an H/KDEL protein with six EF-hand, calcium-binding motifs, found in the endoplasmic reticulum. Our data indicate that RCN1 also is expressed on the cell surface of several endothelial cell lines, including human dermal microvascular endothelial cells (HDMVECs), bone marrow endothelial cells (BMEC), and transformed human bone marrow endothelial cells (TrHBMEC). While RCN1 protein levels were highest in lysates from HDMVEC, this difference was not statistically significant compared BMEC and TrHBMEC. Given preferential adhesion of PCa to bone-marrow EC, these data suggest that RCN1 is unlikely to account for the preferential metastasis of PCa to bone. In addition, there was not a statistically significant difference in total RCN1 protein expression among the PCa cell lines. RCN1 also was expressed on the surface of several PCa cell lines, including those of the LNCaP human PCa progression model and the highly metastatic PC-3 cell line. Interestingly, RCN1 expression on the cell surface was upregulated by tumor necrosis factor alpha treatment of bone-marrow endothelial cells. Taken together, we show cell surface localization of RCN1 that has not been described previously for either PCa or BMEC and that the surface expression on BMEC is regulated by pro-inflammatory TNF-alpha.
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PMID:Novel surface expression of reticulocalbin 1 on bone endothelial cells and human prostate cancer cells is regulated by TNF-alpha. 1856 28

Overexpression of REIC/Dkk-3 (a tumor suppressor gene) induces cancer cell apoptosis through endoplasmic reticulum (ER) stress. Therefore, the identification of the portion of REIC/Dkk-3 that causes ER stress may be essential for the development of cancer treatment based on REIC/Dkk-3. Here, we made several truncated forms of REIC/Dkk-3 and investigated their therapeutic potentials against prostate cancer. Among three truncated forms, a variant comprising the N-terminal 78 amino acid region of REIC/Dkk-3 ((1-78)REIC/Dkk-3) most strongly induced ER stress and apoptosis in human prostate cancer cells (PC3). For in vivo gene expression, we coupled a biodegradable polymer with naked DNA, which attained robust trans-gene expression in PC3-derived subcutaneous tumor. In therapeutic experiments, we demonstrated that multiple direct injections of polymer-conjugated (1-78)REIC/Dkk-3 plasmid provoke ER stress and significantly reduced the subcutaneous tumor volume compared with the control group. We suggest this non-viral strategy may be an effective alternative to viral gene therapy.
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PMID:An N-terminal 78 amino acid truncation of REIC/Dkk-3 effectively induces apoptosis. 1872 18


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