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

---

Query: UMLS:C0376358 (prostate cancer)
59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

FGF7/Keratinocyte growth factor (KGF) regulates the differentiation and development of the prostate epithelium, while over-expression of FGF8 and FGF1 are implicated in carcinogenesis of the prostate. We tested the hypothesis that different members of the FGF family function through different signalling molecules. In prostate DU145 cells, both FGF1 and FGF2 activated ERK1/2 potently and p38 moderately. KGF was however most efficient in inducing p38 activities but had no effect on ERK1/2 function. JNK and STAT activities were not induced by FGFs in prostate cells. In vitro expression of the transcription factors Elk-1 and MEF2A (substrates for ERK1/2 and p38, respectively) for functional quantification, confirmed the pattern of FGF-induced MAPK activations in COS-7 cells. Furthermore, KGF was more efficient than FGF1 and FGF2 in inducing actin stress fibres, and the specific p38 inhibitor SB202190 completely abolished this in a dose-dependent manner. The MEK1/2 inhibitor, U0126, had no effect on FGF-induced stress fibre formation. This study demonstrates the selective activation of MAPK family members by FGFs resulting in activation of transcription factors and stress fibre formation. As multiple FGFs are over-expressed in human prostate cancer, characterization of the distinct signalling pathway by FGFs may reveal new specific targets for therapy.
...
PMID:Keratinocyte growth factor activates p38 MAPK to induce stress fibre formation in human prostate DU145 cells. 1153 48

Environmental signals in the cellular milieu such as hypoxia, growth factors, extracellular matrix (ECM), or cell-surface molecules on adjacent cells can activate signaling pathways that communicate the state of the environment to the nucleus. Several groups have evaluated gene expression or signaling pathways in response to increasing cell density as an in vitro surrogate for in vivo cell-cell interactions. These studies have also perhaps assumed that cells grown at various densities in standard in vitro incubator conditions do not have different pericellular oxygen levels. However, pericellular hypoxia can be induced by increasing cell density, which can exert profound influences on the target cell lines and may explain a number of findings previously attributed to normoxic cell-cell interactions. Thus, we first sought to test the hypothesis that cell-cell interactions as evaluated by the surrogate approach of increasing in vitro cell density in routine normoxic culture conditions results in pericellular hypoxia in prostate cancer cells. Second, we sought to evaluate whether such interactions affect transcription mediated by the hypoxia response element (HRE). Thirdly, we sought to elucidate the signal transduction pathways mediating the induction of HRE in response to cell density induced pericellular hypoxia in routine normoxic culture conditions. Our results indicate that paracrine cell interactions can induce nuclear localization of HIF-1a protein and this translocation is associated with strong stimulation of the HRE-reporter activity. We also make the novel observation that cell density-induced activity of the HRE is dependent on nitric oxide production, which acts as a diffusible paracrine factor secreted by densely cultured cells. These results suggest that paracrine cell interactions associated with pericellular hypoxia lead to the physiological induction of HRE activity via the cooperative action of Ras, MEK1, HIF-1a via pericellular diffusion of nitric oxide. In addition, these results highlight the importance of examining pericellular hypoxia as a possible stimulus in experiments involving in vitro cell density manipulation even in routine normoxic culture conditions.
...
PMID:Cell density mediated pericellular hypoxia leads to induction of HIF-1alpha via nitric oxide and Ras/MAP kinase mediated signaling pathways. 1175 40

The MMP, matrilysin (MMP-7), has been shown to be overexpressed in prostate cancer cells and to increase prostate cancer cell invasion. Prostate stromal fibroblasts secrete factor(s), including fibroblast growth factor-1 (FGF-1) that induces promatrilysin expression in LNCaP cells. In the present study, we investigated the signal transduction pathway involved in the FGF-1-induced expression of promatrilysin. FGF-1 treatment significantly increased the activation of extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2). This induction was time-dependent and was sustained until 24 hours after treatment. Treating the cells with MEK1/2 inhibitor (PD98059) eliminated ERK activation completely and blocked FGF-1-mediated induction of promatrilysin expression. Transient transfection studies with human matrilysin promoter resulted in a four- to five-fold increase in reporter luciferase enzyme activity that was blocked by the MEK1/2 inhibitor (PD98059). Serine phosphorylation of signal transducer and activator of transcription 3 (STAT3) was observed after FGF-1 treatment and pretreatment with 20 microM PD98059-abolished STAT3 phosphorylation. Transient transfection with dominant negative STAT3 inhibited FGF-1-induced transactivation of the matrilysin promoter indicating that STAT3 plays an important role in FGF1-induced matrilysin expression. We propose that the FGF-1-induced signaling pathway that leads to promatrilysin expression is ERK-dependent and leads to phosphorylation of Ser-727 on STAT3, phosphorylated STAT3, then binds and transactivates the matrilysin promoter. Our results demonstrate that ERK-MAP kinase and transcription factor STAT3 are important components of FGF-1-mediated signaling, which induce promatrilysin expression in LNCaP cells.
...
PMID:Fibroblast growth factor-1 induced promatrilysin expression through the activation of extracellular-regulated kinases and STAT3. 1192 92

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.
...
PMID:Activation of MAPK signaling pathway is essential for Id-1 induced serum independent prostate cancer cell growth. 1246 69

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

A loss of functional androgen receptor and an enhanced expression of growth factor receptors and associated ligands are causal genetic events in prostate cancer (PCA) progression. These genetic alterations lead to an epigenetic mechanism where a feedback autocrine loop between membrane receptor and ligand (e.g. EGFR-TGFalpha) results in a constitutive activation of MAPK-Elk1-AP1-mediated mitogenic signaling in human PCA at an advanced and androgen-independent stage. We rationalized that inhibiting these epigenetic events could be useful in controlling advanced PCA growth. Recently, we found that grape seed extract (GSE), a dietary supplement rich in flavonoid procyanidins, inhibits advanced and androgen-independent human PCA DU145 cell growth in culture and nude mice. Here, we performed detailed mechanistic studies to define the effect of GSE on EGFR-Shc-MAPK-Elk1-AP1-mediated mitogenic signaling in DU145 cells. Pretreatment of serum-starved cells with GSE resulted in 70% to almost complete inhibition of EGF-induced EGFR activation and 50% to complete inhibition of Shc activation, which corroborated with a comparable decrease in EGF-induced Shc binding to EGFR. Conversely, EGF-induced ERK1/2 phosphorylation was inhibited only by lower doses of GSE; in fact, higher doses showed an increase. Additional studies showed that GSE alone causes a dose- and time-dependent increase in ERK1/2 phosphorylation in starved DU145 cells that is inhibited by an MEK1 inhibitor PD98059. Independent of this increase in ERK1/2 phosphorylation, GSE showed a strong inhibition of ERK1/2 kinase activity to Elk1 in both cellular and cell-free systems. GSE treatment of cells also inhibited both EGF-induced and constitutively active Elk1 phosphorylation and AP1 activation. GSE treatment also showed DNA synthesis inhibition in starved and EGF-stimulated cells as well as loss of cell viability and apoptotic death that was further increased by adding MEK1 inhibitor. Since GSE strongly induced apoptosis independent of its affect on an increase in phospho-ERK1/2, we hypothesized that apoptotic effect of GSE could be by other mechanism(s) including its effect on stress-associated MAPK, the JNK. Indeed, GSE-treated cells showed a strong and sustained increase in phospho-JNK1/JNK2 levels, JNK activity and phospho-cJun levels. An inhibition of GSE-induced JNK activation by a novel JNK inhibitor SP600125 resulted in a significant reversal of GSE-induced apoptotic death suggesting the involvement of JNK activation by GSE in its apoptosis response. Together, these results suggest that anticancer effects of GSE in PCA be mediated via impairment of EGFR-ERK1/2-Elk1-AP1-mediated mitogenic signaling and activation of JNK causing growth inhibition and apoptosis, respectively.
...
PMID:Grape seed extract inhibits EGF-induced and constitutively active mitogenic signaling but activates JNK in human prostate carcinoma DU145 cells: possible role in antiproliferation and apoptosis. 1261 55

Transforming growth factor (TGF)-beta1 acts as a potent growth inhibitor of prostate epithelial cells, and aberrant function of its receptor type I and II correlates with tumor aggressiveness. However, intracellular and serum TGF-beta1 levels are elevated in prostate cancer patients and further increased in patients with metastatic carcinoma, suggesting the oncogenic switch of TGF-beta1 role in prostate tumorigenesis. Recently, we reported the mitogenic conversion of TGF-beta1 effect by oncogenic Ha-Ras in prostate cancer cells. Here, we show that TGF-beta1 activates interleukin (IL)-6, which has been implicated in the malignant progression of prostate cancers, via multiple signaling pathways including Smad2, nuclear factor-kappaB (NF-kappaB), JNK, and Ras. TGF-beta1-induced IL-6 gene expression was strongly inhibited by DN-Smad2 but not by DN-Smad3 while it was further activated by wild-type Smad2 transfection. IL-6 activation by TGF-beta1 was accompanied by nuclear translocation of NF-kappaB, which was blocked by the p38 inhibitors SB202190 and SB203580 or by IkappaBalphaDeltaN transfection, indicating the crucial role for the p38-NF-kappaB signaling in TGF-beta1 induction of IL-6. TGF-beta1 activated c-Jun phosphorylation, and IL-6 induction by TGF-beta1 was severely impeded by DN-c-Jun and DN-JNK or AP-1 inhibitor curcumin, showing that the JNK-c-Jun-AP-1 signaling plays a pivotal role in TGF-beta1 stimulation of IL-6. It was also found that the Ras-Raf-MEK1 cascade is activated by TGF-beta1 and participates in the TGF-beta1 induction of IL-6 in an AP-1-dependent manner. Cotransfection assays demonstrated that TGF-beta1 stimulation of IL-6 results from the synergistic collaboration of the Smad2, p38-NF-kappaB, JNK-c-Jun-AP-1, or Ras-Raf-MEK1 cascades. In addition, a time course IL-6 decay revealed that mRNA stability of IL-6 is modestly increased by TGF-beta1, indicating that TGF-beta1 also regulates IL-6 at the post-transcriptional level. Intriguingly, IL-6 inactivation restored the sensitivity to TGF-beta1-mediated growth arrest and apoptosis, suggesting that elevated IL-6 in advanced prostate tumors might act as a resistance factor against TGF-beta1. Collectively, our data demonstrate that IL-6 expression is stimulated by tumor-producing TGF-beta1 in human prostate cancer cells through multiple signaling pathways including Smad2, p38, JNK, and Ras, and enhanced expression of IL-6 could contribute to the oncogenic switch of TGF-beta1 role for prostate tumorigenesis, in part by counteracting its growth suppression function.
...
PMID:Transforming growth factor-beta1 activates interleukin-6 expression in prostate cancer cells through the synergistic collaboration of the Smad2, p38-NF-kappaB, JNK, and Ras signaling pathways. 1285 69

Prostate carcinoma-derived factors induce a proliferative response in osteoblasts. The present study investigated the involvement of MAP kinase in the osteoblastic reaction of osteocytes and the response of 1alpha,25-hydroxy-vitamin D3 (1,25-vitD3)-pretreated osteoblasts. Conditioned media (CM) from prostate, colon, pancreatic, renal cell and breast cancer cell lines were tested on their proliferative activity using murine osteoblast-like MC3T3-E1 cells, MG63 human osteosarcoma cells and immortalized human osteoblasts (AHTO-7). Changes in osteoblastic activities of the supernantants were measured in the presence of MAP kinase inhibitors and following 1,25-vitD3-induced differentiation of the target osteoblasts. Supernatants of prostate cancer cells stimulated proliferation of osteoblasts in all three indicator cell lines, with AHTO-7 exhibiting the most significant correlation to human primary osteoblast cultures. 1,25-vitD3 induced the differentiation marker alkaline phosphatase (ALP) in MC3T3-E1 and AHTO-7, but only to a minor degree in MG63 cells. 1,25-vitD3-induced differentiation reduced the proliferative response to CM from several cell lines in MC3T3-E1 and MG63 to a minor degree, whereas in AHTO-7 cells the osteoblastic reaction was reduced for 2/4 pancreatic, 3/3 colon and 1/1 renal cancer CMs, however not for 3/3 prostate cancer CMs. Stimulation of AHTO-7 cells by CM from prostate cancer lines is inhibited significantly by MEK1 kinase inhibitor PD 98059 in contrast to CMs derived from other carcinomas, except ACHN renal cancer cells. The findings in the present study demonstrate that human AHTO-7 cells seem to represent a valid human system to monitor osteoblastic activity, especially in respect to 1,25-vitD3-induced differentiation. Vitamin D3-induced differentiation has no direct effect on prostate cancer-derived osteoblastic activity in the same cell line in vitro, which however, could be reversed by disruption of the signal transduction at the MAP kinase level, revealing a new target for the inhibition of prostate cancer-associated bone formation.
...
PMID:Effects of 1alpha,25-dihydroxy-vitamin D3 pretreatment and MAP kinase inhibitor PD 98059 on response of osteoblasts to prostate-derived osteoblastic factors. 1288 36

Because ErbB-2 receptor is involved in hormone-independency for growth and metastasis of prostate cancer cells, the aim was to investigate the effects of quercetin on ErbB-2 and ErbB-3 expression and its critical components such as MAP kinase and PI-3 kinase. Hemocytometric counts and [3H]-thymidine incorporation were used to determine the effects of quercetin, EGF and TGF-alpha on cell proliferation and DNA synthesis in PC-3 and LnCap cells. Changes in ErbB-2, ErbB-3 and components of MAPK and PI-3K pathways were analyzed by Western blot analysis. Treatment of PC-3 and LnCap cells with quercetin resulted in a dose-dependent growth inhibition. The rate of DNA synthesis was decreased by 40, 55 and 65% on treatment with 14.5, 29.0 and 58.0 microM of quercetin, respectively. Concomitantly, these treatments led to a dose-dependent decrease in ErbB-2, ErbB-3 and their basal autophosphorylation levels as compared to controls. Cyclin D1 expression and basal phosphorylation of c-Raf, MAPK, Elk-1 and Akt-1 in PC-3 cells was also inhibited by quercetin treatment. Co-treating PC-3 cells with quercetin significantly attenuated EGF- and TGF-alpha-induced growth and phosphorylation of ErbB-2, ErbB-3, c-Raf, MAPK kinase 1/2 (MEK1/2), MAPK, Elk-1 and Akt-1. Since ErbB receptor is important for growth, metastasis and drug resistance, inhibition of ErbB-2 and ErbB-3 by pharmacological doses of quercetin may provide a new approach for treatment of prostate cancers.
...
PMID:Inhibition of ErbB-2 and ErbB-3 expression by quercetin prevents transforming growth factor alpha (TGF-alpha)- and epidermal growth factor (EGF)-induced human PC-3 prostate cancer cell proliferation. 1288 23

Cadmium exposure increases the risk of prostate cancer. We now describe the effects of Cd2+ on signalling and proliferation in 1LN prostate cells. Cd2+ increased [3H]thymidine uptake and cell number twofold. Cd2+ elevated intracellular IP3, cytosolic-free Ca2+, phosphorylated MEK1/2, ERK1/2, p38 MAPK and JNK two- to threefold. Increased PDK1 and phosphorylation of the 85-kDa regulatory subunit of PI 3-kinase, Akt and p70s6k were also observed. Cd2+ treatment increased transcription factors NFkappaB and CREB, and the expression of c-fos and c-myc. Cd2+-induced increased uptake of [3H]thymidine was abolished by translational and transcriptional inhibitors, and Ca2+ channel blockers. Inhibition of phospholipase C and of Ca2+ binding to IP3 receptors inhibited Cd2+-induced DNA synthesis as did inhibition of tyrosine kinases, protein kinase C, PI 3-kinase, farnesyl transferase, MEK1/2, ERK1/2 and p38MAPK. Thus signalling events, which are triggered on exposure of 1LN cells to submicromolar concentrations of Cd2+, induce increased proliferation of these cells.
...
PMID:Induction of mitogenic signalling in the 1LN prostate cell line on exposure to submicromolar concentrations of cadmium+. 1449 49


1 2 3 4 5 6 Next >>

---