Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-6 (IL-6) is a multifunctional cytokine that activates the signaling pathways of Janus kinases-signal transducers and activators of transcription (STAT) and/or mitogen-activated protein kinases (MAPK) in various tumors. Thus, it modulates cell growth and apoptosis. IL-6 levels are elevated in tissues and sera from prostate cancer patients and IL-6 receptor expression has been detected in prostate cancer cell lines and clinical specimens. Continuous exposure of prostate cancer cells to IL-6 might alter their responsiveness to this cytokine. To gain more insight into the function of IL-6 in prostate carcinoma, we have inoculated LNCaP-IL-6+ cells, generated after prolonged treatment with IL-6, into nude mice (total n = 16, two independent experiments). Controls included animals bearing LNCaP-IL-6- cells, passaged at the same time as LNCaP-IL-6+ cells without supplementation of IL-6. LNCaP-IL-6+ tumor volumes were larger than those of their counterparts at all time points. There were no signs of cachexia in any of the experimental animals and all mice were free of metastases. To better understand the mechanisms responsible for accelerated growth of LNCaP-IL-6+ tumors, we have investigated the expression of cell-cycle regulatory molecules by Western blot analysis. The levels of cyclin-dependent kinase 2 were elevated in LNCaP-IL-6+ cells. There was a strong down-regulation of cyclins D1 and E in the LNCaP-IL-6+ subline. The cell-cycle inhibitor p27 was expressed at a low level in LNCaP-IL-6+ cells and could not be up-regulated by addition of IL-6. Most notably, LNCaP-IL-6+ cells exhibited a reduced expression of the hypophosphorylated form of the retinoblastoma protein (pRb). Accelerated tumor growth in our model system was also associated with alterations in IL-6-signaling pathways. The ability of IL-6 to induce tyrosine phosphorylation of STAT3 was abolished in the LNCaP-IL-6+ subline. In contrast, the levels of the MAPK extracellular signal-regulated kinases 1/2 increased in cells generated after long-term IL-6 treatment. The inhibitor of MAPK kinase PD 98059 retarded the proliferation of LNCaP-IL-6+ but not that of control cells. In summary, we show in the present study that chronic exposure of prostate cancer cells to IL-6 facilitates tumor growth in vivo by abolishment of the growth control by pRb and activation of the MAPK signaling pathway. These findings could be relevant to understand the role of IL-6 in prostate cancer progression.
 ...
PMID:Accelerated in vivo growth of prostate tumors that up-regulate interleukin-6 is associated with reduced retinoblastoma protein expression and activation of the mitogen-activated protein kinase pathway. 1254 23

The expression and secretion of prostate-specific antigen (PSA) are regulated by androgens in normal prostate secretory epithelial cells. In prostate cancer patients, the serum PSA level is usually elevated and cancer cells are initially responsive to androgens. However, those cancer cells become androgen-independent after androgen ablation therapy. In hormone-refractory cancer patients, even in an androgen-deprived environment, the circulation level of PSA rebounds and is constitutively elevated through a yet unknown mechanism. Tyrosine phosphorylation of ErbB-2 is involved in regulating the androgen-responsive phenotype of prostate cancer cells, and it is at least partly regulated by the cellular form of prostatic acid phosphatase (PAcP), a prostate-unique protein tyrosine phosphatase. We investigated the ErbB-2 signal pathway in androgen-independent PSA secretion. LNCaP C-81 cells, which are androgen-independent LNCaP cells lacking endogenous PAcP expression with a hypertyrosine phosphorylated ErbB-2, secreted a higher level of PSA in conditioned media than did androgen-sensitive LNCaP C-33 parental cells. A restored expression of cellular PAcP in C-81 cells was concurrent with a decrease in tyrophosphorylation of ErbB-2 and reduction of PSA secretion. Moreover, transient transfection of C-33 cells with the wild-type ErbB-2 or a constitutively active mutant of MEK1 cDNA resulted in an increased level of secreted PSA. The elevation of secreted PSA level by the forced expression of ErbB-2 was inhibited by an MEK inhibitor, PD98059. In C-81 cells, the expression of a dominant negative mutant of ErbB-2 reduced the secreted level of PSA. The inhibition of ErbB-2 or mitogen-activated protein (MAP) kinases by specific inhibitors AG879, AG825, or PD98059 led to a decrease in PSA secretion. Taken together, our data clearly indicate that the ErbB-2 signal pathway via MAP kinases (ERK1/2) is involved in regulating the secretion of PSA by androgen-independent human prostate cancer LNCaP C-81 cells in an androgen-depleted environment.
 ...
PMID:ErbB-2 signaling is involved in regulating PSA secretion in androgen-independent human prostate cancer LNCaP C-81 cells. 1256 72

Progression of prostate cancer ultimately results in a disease that is refractory to hormone ablation therapy but nevertheless continues to require the androgen receptor. Progression to hormone refractory disease is often correlated with overexpression of growth factors and receptors capable of establishing autocrine and/or paracrine growth-stimulatory loops. Many of these growth factor receptors engage the Ras/mitogen-activated protein (MAP) kinase pathway as part of their signaling activities. This raises the possibility that chronic activation of Ras/MAP kinase signaling could cause or contribute to the progression of prostate cancer. We have demonstrated previously that MAP kinase activation correlates with the progression to advanced hormone refractory disease in patient samples. Here we demonstrate that stable expression of Ras effector-loop mutants that activate the Ras/MAP kinase pathway is sufficient to reduce the androgen requirement of LNCaP prostate cancer cells for growth, prostate-specific antigen expression, and tumorigenicity. We propose that chronic activation of endogenous c-Ras by autocrine and paracrine growth factor stimulation sensitizes the androgen receptor transcriptional complex to subphysiological levels of androgen. This provides a common mechanism for prostate cancer progression driven by diverse agonists.
 ...
PMID:Constitutive activation of the Ras/mitogen-activated protein kinase signaling pathway promotes androgen hypersensitivity in LNCaP prostate cancer cells. 1270 92

The mechanisms by which androgens stimulate proliferation of prostate cancer cells are poorly understood. It has been proposed that androgen stimulation may induce the mitogen-activated protein (MAP) kinase system in prostate cancer cells and lead to cellular proliferation. We attempted to evaluate the role of the extracellular signal-regulated kinase (ERK) pathway in the stimulation by androgens of prostate cancer cell proliferation. Androgen-sensitive prostate cancer cell line (LNCaP) cells plated on sterile glass coverslips were treated with 10(-8) M dihydrotestosterone (DHT) or epidermal growth factor (EGF) (10 ng/ml) for periods ranging from 1 min to 96 h. The proliferative index of the cells, evaluated by immunoperoxidase staining of cells with an antibody to Ki-67, was increased at least two-fold at all time points from 5 min to 48 h following exposure to either DHT or EGF. Immunohistochemical evaluation of ERK1/2 and pERK (activated ERK) demonstrated high levels of ERK1/2 in untreated LNCaP cells, while pERK was expressed at much lower levels. Following treatment with DHT, no change in staining intensity for either ERK1/2 or pERK was observed, while treatment with EGF resulted in no change in ERK1/2, but significantly increased cytoplasmic staining for pERK at all time points beyond 2 min. These results were confirmed by Western blot analysis of ERK1/2 and pERK expression in these cell lines following treatment with DHT or EGF. Our findings suggest that the proliferative response of prostate cancer cells to androgens, unlike the proliferative response to EGF, is not mediated by the activation of ERK1/2, and that currently undefined pathways other than those involving ERK1/2 are involved.
 ...
PMID:The response of extracellular signal-regulated kinase (ERK) to androgen-induced proliferation in the androgen-sensitive prostate cancer cell line, LNCaP. 1271 36

Bombesin and its mammalian homologue gastrin-releasing peptide have been shown to be highly expressed and secreted by neuroendocrine cells in prostate cancer, and are thought to be related to the carcinogenesis and progression of this disease. We found, in this study, bombesin specifically induced mitogen-activated protein (MAP) kinase activation as shown by increased extracellular regulated kinase (ERK) phosphorylation and epidermal growth factor (EGF) receptor transactivation in prostate cancer cells, which express functional gastrin-releasing peptide receptor. The transactivation of EGF receptor was required for bombesin-induced ERK phosphorylation. Furthermore, non-receptor tyrosine kinase Src and cellular Ca2+ were shown to be involved in bombesin-induced EGF receptor transactivation and ERK phosphorylation. Inhibition of either EGF receptor transactivation or ERK activation blocked bombesin-induced DNA synthesis in these cells. Taken together, these data suggest bombesin may act as a mitogen in prostate cancer by activating MAP kinase pathway via EGFR transactivation.
 ...
PMID:Activation of extracellular signal-regulated kinase mediates bombesin-induced mitogenic responses in prostate cancer cells. 1287 8

AMP-activated protein kinase (AMPK) functions as an energy sensor to provide metabolic adaptations under the ATP-deprived conditions such as hypoxia. In the present study, we considered a role of AMPK in the adaptive response to hypoxia by examining whether AMPK is involved in the regulation of hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcription factor that is critical for hypoxic induction of physiologically important genes. We demonstrate that hypoxia or CoCl2 rapidly activated AMPK in DU145 human prostate cancer cells, and its activation preceded the induction of HIF-1 alpha expression. Under these conditions, blockade of AMPK activity by a pharmacological or molecular approach significantly attenuated hypoxia-induced responses such as HIF-1 target gene expression, secretion of vascular endothelial growth factor, glucose uptake, and HIF-1-dependent reporter gene expression, indicating that AMPK is critical for the HIF-1 transcriptional activity and its target gene expression. Its functional requirement for HIF-1 activity was also demonstrated in several different cancer cell lines, but AMPK activation alone was not sufficient to stimulate the HIF-1 transcriptional activity. We further present data showing that AMPK transmits a positive signal for HIF-1 activity via a signaling pathway that is independent of phosphatidylinositol 3-kinase/AKT and several mitogen-activated protein kinases. Taken together, our results suggest that AMPK is a novel and critical component of HIF-1 regulation, implying its new roles in oxygen-regulated cellular phenomena.
 ...
PMID:AMP-activated protein kinase activity is critical for hypoxia-inducible factor-1 transcriptional activity and its target gene expression under hypoxic conditions in DU145 cells. 3044 3

Septic shock is the most common cause of death in intensive care units, and no effective treatment is available at present. Lipopolysaccharide (LPS) is the primary mediator of Gram-negative sepsis by inducing the production of macrophage-derived proinflammatory cytokines, in which activation of nuclear factor-kappaB (NF-kappaB) plays an important role. PC-SPES is an eight-herb mixture active against a variety of malignancies, including prostate cancer and leukemia. In this study, we demonstrated that PC-SPES inhibited the LPS-induced NF-kappaB reporter activity in RAW264.7 macrophages. Electrophoretic mobility shift assay showed that PC-SPES inhibited the binding of NF-kappaB to specific DNA sequences; however, it did not affect either degradation of inhibitory kappaBalpha or nuclear translocation of NF-kappaB. Also, we explored the effect of PCSPES on LPS-induced mitogen-activated protein (MAP) kinase signaling; PC-SPES did not affect LPS-induced phosphorylation of MAP kinases, including c-Jun NH2-terminal kinase, p38, and extracellular signal-regulated kinase 1/2. Moreover, PC-SPES decreased the production of proinflammatory cytokines and inducible enzymes, such as tumor necrosis factor (TNF) alpha, interleukin (IL)-1beta, IL-6, cyclooxygenase-2, as well as inducible nitric-oxide synthase in RAW264.7 macrophages and peritoneal macrophages from C57BL/6 mice after the cells were stimulated by either LPS or LPS and interferon-gamma. Furthermore, PC-SPES rescued C57BL/6 mice from death caused by LPS-induced septic shock in conjunction with decreased serum levels of TNFalpha and IL-1beta. Together, PC-SPES is a potent inhibitor of NF-kappaB and might be useful for the treatment of sepsis and inflammatory diseases.
 ...
PMID:PC-SPES: a potent inhibitor of nuclear factor-kappa B rescues mice from lipopolysaccharide-induced septic shock. 1464 83

Prostate cancer (PCA) is the second most frequently diagnosed and leading cause of cancer-related deaths in men in the USA. The recognition that matrix metalloproteinases (MMPs) facilitate tumor cell invasion and metastasis of PCA has led to the development of MMP inhibitors as cancer therapeutic agents. As part of our efforts to develop newer and effective chemopreventive agents for PCA, we evaluated the effect of proanthocyanidins from grape seeds (GSP) on metastasis-specific MMP-2 and -9 in human prostate carcinoma DU145 cells by employing western blot and gelatinolytic zymography. Treatment of GSP dose-dependently inhibited cell proliferation (15-100% by 5-80 microg/ml of GSP), viability (30-80% by 20-80 microg/ml of GSP) and fibroblast conditioned medium (FCM)-induced expression of MMP-2 and -9 in DU145 cells. Since the signaling cascade of mitogen-activated protein kinases (MAPK) have been shown to regulate the expression of MMPs in tumor cells, we found that the treatment of DU145 cells with GSP (20-80 microg/ml) resulted in marked inhibition of FCM-induced phosphorylation of extracellular signal regulated kinase (ERK)1/2 and p38 but had little effect on c-Jun N-terminal kinase under similar experimental conditions. GSP treatment (20-80 microg/ml) to DU145 cells also dose-dependently inhibited FCM-induced activation of NF kappa B concomitantly with inhibition of MMP-2 and -9 expression in the same system. Additionally, the treatment of inhibitors of MEK (PD98059) and p38 (SB203580) to DU145 cells resulted in the reduction of FCM-induced phosphorylation of ERK1/2 and p38 concomitantly marked reduction in MMP-2 and -9 expressions. In further studies, treatment of androgen-sensitive LNCaP cells with a synthetic androgen R1881, resulted in an increase of MMP-2 and -9, which were completely abrogated in the presence of GSP (20-60 microg/ml). These data suggest that inhibition of metastasis-specific MMPs in tumor cells by GSP is associated with the inhibition of activation of MAPK and NF kappa B pathways, and thus provides the molecular basis for the development of GSP as a novel chemopreventive agent for both androgen-sensitive and -insensitive prostate cancer therapies.
 ...
PMID:Proanthocyanidins from grape seeds inhibit expression of matrix metalloproteinases in human prostate carcinoma cells, which is associated with the inhibition of activation of MAPK and NF kappa B. 2253 77

We previously discovered that a fat-metabolizing enzyme, 15-lipoxygenase-1 (15-LO-1), is high in human prostate cancer (PCa) and correlates with disease progression. The biologic link between the aberrant 15-LO-1/linoleic acid (LA) metabolism and fat (which is a rich source of growth factors) in PCa is unknown. Therefore, we tested the hypothesis that the metabolic product of the polyunsaturated fatty acid LA (i.e., 13-S-hydroxyoctadecadienoic acid or 13-(S)-HODE) affects the proliferation status of PCa cells through one or more growth factors. We used parental prostate cancer cell line-3 (PC-3) and engineered PC-3 cell lines [PC3-Zeo (mock-transfected), PC3-15LOS (15-LO-1-overexpressing), and PC3-15LOAS (15-LO-1-blocked)] to test our hypothesis. Of the growth factors examined, only insulin-like growth factor-1 (IGF-1) exhibited a two-fold to three-fold increase in growth response on PC3-15LOS cells compared to PC3-Zeo (control) cell line (P <.01). Insulin-like growth factor-1 receptor (IGF-1R) immunohistochemical analyses of human normal and adenocarcinoma prostate tissues, as well as levels in tumors derived from nude mice injected with PC-3 cells, demonstrated that elevated IGF-1R expression correlated with 15-LO-1 levels. Radioligand binding assays demonstrated two-fold higher IGF-1 binding sites in PC3-15LOS cells (P <.05 vs PC3-Zeo cells). IGF-1R promoter reporter assay and affinity-purified IGF-1R receptor levels demonstrated a four-fold higher activity in PC3-15LOS cells (P <.01 vs PC3-Zeo cells). IGF-1R promoter activation is 13-(S)-HODE-dependent. IGF-1R blockade with a dominant-negative adenovirus caused significant growth inhibition in PC-3 cells (P <.0001; PC3-15LOAS versus PC3-15LOS cells), as well as affected the IGF-1-stimulated mitogen-activated protein (MAP) kinase (Erk1/2) and Akt activation levels. Our study suggests that overexpression of 15-LO-1 in PCa contributes to the cancer progression by regulating IGF-1R expression and activation.
 ...
PMID:15-lipoxygenase-1 expression upregulates and activates insulin-like growth factor-1 receptor in prostate cancer cells. 1506 70

Genistein, a component of soy, has been reported to protect against spontaneously developing prostate tumors in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. This is consistent with reports showing that Asians eating a diet high in soy have reduced incidence of clinically manifested prostate cancer. In order to understand the mechanism of action of genistein, we have investigated the expression of androgen and estrogen receptors, four growth factor receptors that signal via tyrosine protein kinases, and specific growth factor proteins in the dorsolateral prostates of TRAMP mice fed 250 mg genistein/kg diet, starting at 5 weeks of age. These analyses were carried out at 12 weeks, prior to the development of solid tumors, allowing us to readily investigate cell proliferation and biomarkers in premalignant tissue. Cell proliferation, AR, ER-alpha, EGFR, ErbB2, EGF, IGF-1R, IGF-1, VEGFR2, ERKs-1 and 2 proteins and TGF-alpha mRNA, but not ER-beta and VEGF, were significantly increased in prostates of TRAMP compared to C57BL/6 mice. Genistein in the diet significantly down-regulated cell proliferation, EGFR, IGF-1R, ERK-1 and ERK-2, but not AR, ER-alpha, ER-beta, ErbB2, EGF, TGF-alpha, IGF-1, VEGF and VEGFR in prostates of TRAMP mice. Serum testosterone and dihydrotestosterone concentrations were not significantly different in C57BL/6 or TRAMP male mice fed control or genistein-containing diets. The up-regulation of sex steroid receptors and multiple growth signaling pathways in TRAMP mice supports the concept of multiple dysregulation contributing to carcinogenesis. Down-regulation of the tyrosine kinase regulated proteins, EGFR and IGF-1R, and of the downstream mitogen-activated protein kinases, ERK-1 and 2, with genistein in the diet provides a possible mechanism for prostate cancer chemoprevention.
 ...
PMID:Genistein alters growth factor signaling in transgenic prostate model (TRAMP). 1514 38


<< Previous 1 2 3 4 5 6 7 8 9 Next >>