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)

Both hyaluronidase and transforming growth factor (TGF)-beta 1 play a significant role in the development of prostate cancer. In this study, the regulation of tumor necrosis factor (TNF)-mediated cell death by hyaluronidase and TGF-beta 1 was investigated. Preexposure of L929 fibroblasts, prostate LNCaP cells, and epithelial Mv 1 Lu cells to hyaluronidase for a minimum of 12 h resulted in significant enhancement of cell death by TNF. Phosphorylation of p42 and p44 mitogen-activated-protein (MAP) kinases was found by stimulation of L929 cells with hyaluronidase for 30 min, indicating that the Raf/MAP kinase-extracellular signal-regulating protein kinase (MEK)/ MAP kinase pathway was activated. However, blocking the activation of upstream MAP kinase kinase (MEK 1 and 2 kinase) by PD-98059 failed to inhibit the hyaluronidase-enhanced TNF killing of cells, suggesting that hyaluronidase-mediated degradation of extracellular matrix and membrane components may elicit multiple signaling pathways. As a potent stimulator of extracellular matrix protein synthesis, TGF-beta 1 blocked the hyaluronidase-enhanced death of L929 and LNCaP cells mediated by TNF. TGF-beta 1 activated protein-tyrosine kinases in L929 cells, in which the tyrosine kinase inhibitors lavendustin A and tyrphostin blocked the activation as well as the TGF-beta 1 inhibition of hyaluronidase effects. Functional antagonism was also observed between hyaluronidase and TGF-beta 1 in cell growth regulation. For example, TGF-beta 1-mediated suppression of epithelial Mv 1 Lu cell growth was abolished by hyaluronidase. Overall, it is demonstrated in this study that hyaluronidase reciprocally antagonized TGF-beta 1 in the modulation of cell proliferation and TNF-mediated death.
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PMID:Hyaluronidase enhancement of TNF-mediated cell death is reversed by TGF-beta 1. 943 5

Epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) are potent mitogens that regulate proliferation of prostate cancer cells via autocrine and paracrine loops and promote tumor metastasis. They exert their action through binding to the corresponding cell surface receptors that initiate an intracellular phosphorylation cascade, leading to the activation of mitogen-activated protein kinases (MAPKs), which recruit transcription factors. We have studied the effects of EGF, IGF-I, and the protein kinase A (PKA) activator forskolin on the activation of p42/ extracellular signal-regulated kinase (ERK)2, which is a key kinase in mediation of growth factor-induced mitogenesis in prostate cancer cells. The activity of p42/ERK2 was determined by immune complex kinase assays and by immunoblotting using a phospho p44/p42 MAPK-specific antibody. EGF, IGF-I, and forskolin-induced PKA activity stimulate intracellular signaling pathways converging at the level of p42/ERK2. In the androgen-insensitive DU145 cell line, there is a constitutive basal p42/ ERK2 activity that is not present in androgen-sensitive LNCaP cells. Constitutive p42/ERK2 activity is abrogated by blockade of the EGF receptor. Hence, it is obviously caused by an autocrine loop involving this receptor. The effects of EGF on p42/ERK2 are potentiated by forskolin in both cell lines. The blockade of PKA by the specific inhibitor H89 attenuates this synergism. This finding is in contrast to those obtained in several other systems studied thus far, in which PKA activators inhibited MAPKs. p42/ERK2 in DU145 cells is highly responsive to IGF-I stimulation, whereas no effect of IGF-I on p42/ERK2 can be measured in LNCaP cells. Moreover, our results demonstrate that selective blockade of the EGF receptor in prostate cancer cells does not only inhibit the action of EGF, but also IGF-I-induced activation of the MAPK pathway and the interaction with the PKA pathway. In conclusion, these findings offer new possibilities for a therapeutical intervention in prostate cancer by targeting signaling pathways of growth factors and PKA.
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PMID:Epidermal growth factor (EGF) receptor blockade inhibits the action of EGF, insulin-like growth factor I, and a protein kinase A activator on the mitogen-activated protein kinase pathway in prostate cancer cell lines. 989 11

The androgen receptor (AR) binds to and activates transcription of target genes in response to androgens. In an attempt to isolate cofactors capable of influencing AR transcriptional activity, we used an immunoprecipitation method and identified a 44-kDa protein, designated p44, as a new AR-interacting protein. p44 interacts with AR in the nucleus and with an androgen-regulated homeobox protein (NKX3.1) in the cytoplasm of LNCaP cells. Transient-transfection assays revealed that p44 enhances AR-, glucocorticoid receptor-, and progesterone receptor-dependent transcription but not estrogen receptor- or thyroid hormone receptor-dependent transcription. p44 was recruited onto the promoter of the prostate-specific antigen gene in the presence of the androgen in LNCaP cells. p44 exists as a multiprotein complex in the nuclei of HeLa cells. This complex, but not p44 alone, enhances AR-driven transcription in vitro in a cell-free transcriptional system and contains the protein arginine methyltransferase 5, which acts synergistically with p44 to enhance AR-driven gene expression in a methyltransferase-independent manner. Our data suggest a novel mechanism by which the protein arginine methyltransferase is involved in the control of AR-driven transcription. p44 expression is dramatically enhanced in prostate cancer tissue compared with adjacent benign prostate tissue.
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PMID:Purification and identification of a novel complex which is involved in androgen receptor-dependent transcription. 1297 18

R-etodolac, a nonsteroidal anti-inflammatory drug, inhibits the progression of CWRSA6 androgen-independent and LuCaP-35 androgen-dependent prostate cancer xenograft growth through downregulation of cyclin D1 expression via the PPARgamma pathway. PPARgamma protein degradation, observed post-R-etodolac treatment, resulted from phospho-MAP kinase (p44/42) induction by R-etodolac negatively regulating PPARgamma function. Negative regulation of PPARgamma was overcome by a combination regimen of R-etodolac with the HER-kinase axis inhibitor, rhuMab 2C4, which demonstrated an additive antitumor effect. We further show that the inhibition of HER-kinase activity by rhuMab 2C4 is sufficient to inhibit PPARgamma protein degradation. This study introduces a novel concept of an in vivo crosstalk between the HER-kinase axis and PPARgamma pathways, ultimately leading to negative regulation of PPARgamma activity and tumor growth inhibition.
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PMID:Inhibition of HER-kinase activation prevents ERK-mediated degradation of PPARgamma. 1519 59

Various hormones and growth factors have been implicated in progression of prostate cancer, but their role and the underlying molecular mechanism(s) involved remain poorly understood. In this study, we investigated the role of human growth hormone (GH) and its receptor (GHR) in human prostate cancer. We first demonstrated mRNA expression of GHR and of its exon 9-truncated isoform (GHR(tr)) in benign prostate hyperplasia (BPH) and prostate adenocarcinoma patient tissues, as well as in LNCaP, PC3 and DU145 human prostate cancer cell lines. GHR mRNA levels were 80% higher and GHR(tr) only 25% higher, in the carcinoma tissues than in BPH. Both isoforms were also expressed in LNCaP and PC3 cell lines and somewhat less so in DU145 cells. The LNCaP cell GHR protein was further characterized, on the basis of its M(r) of 120kDa, its binding to two different GHR monoclonal antibodies, its high affinity and purely somatogenic binding to (125)I-hGH and its ability to secrete GH binding protein, all characteristic of a functional GHR. Furthermore, GH induced rapid, time- and dose-dependent signaling events in LNCaP cells, including phosphorylation of JAK2 tyrosine kinase, of GHR itself and of STAT5A (JAK2-STAT5A pathway), of p42/p44 MAPK and of Akt/PKB. No effect of GH (72h) could be shown on basal or androgen-induced LNCaP cell proliferation nor on PSA secretion. Interestingly, however, GH caused a rapid (2-12h) though transient striking increase in immunoreactive androgen receptor (AR) levels (< or =5-fold), followed by a slower (24-48h) reduction (< or = 80%), with only modest parallel changes in serine-phosphorylated AR. In conclusion, the GH-induced activation of signaling pathways, its effects on AR protein in LNCaP cells and the isoform-specific regulation of GHR in prostate cancer patient tissues, suggest that GH, most likely in concert with other hormones and growth factors, may play an important role in progression of human prostate cancer.
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PMID:Growth hormone (GH) receptors in prostate cancer: gene expression in human tissues and cell lines and characterization, GH signaling and androgen receptor regulation in LNCaP cells. 1519 5

Hepatocyte growth factor/scatter factor-Met signaling has been implicated in tumor growth, invasion, and metastasis. Suppression of this signaling pathway by targeting the Met protein tyrosine kinase may be an ideal strategy for suppressing malignant tumor growth. Using RNA interference technology and adenovirus vectors carrying small-interfering RNA constructs (Ad Met small-interfering RNA) directed against mouse, canine, and human Met, we can knock down c-met mRNA. We show a dramatic dependence on Met in both ligand-dependent and ligand-independent mouse, canine, and human tumor cell lines. Mouse mammary tumor (DA3) cells and Met-transformed NIH3T3 (M114) cells, as well as both human and canine prostate cancer (PC-3 and TR6LM, human sarcoma (SK-LMS-1), glioblastoma (DBTRG), and gastric cancer (MKN45) cells, all display a dramatic reduction of Met expression after infection with Ad Met small-interfering RNA. In these cells, we observe suppression of tumor cell growth and viability in vitro as well as inhibition of hepatocyte growth factor/scatter factor-mediated scattering and invasion in vitro, whether Met activation was ligand dependent or not. Importantly, Ad Met small-interfering RNA led to apoptotic cell death in many of the tumor cell lines, especially DA3 and MKN45, but did not adversely affect MDCK canine kidney cells. Met small-interfering RNA also abrogated downstream Met signaling to molecules such as Akt and p44/42 mitogen-activated protein kinase. We further show that intratumoral infection with c-met small-interfering RNA adenovirus results in a substantial reduction in tumor growth. Thus, Met small-interfering RNA adenoviruses are reliable tools for studying Met function and raise the possibility of their application for cancer therapy.
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PMID:RNA interference reveals that ligand-independent met activity is required for tumor cell signaling and survival. 1552 Feb 3

Prostate cancer is the second leading cause of cancer deaths in men. Conventional therapies produce a high rate of cure for patients with localized prostate cancer, but there is no cure once the disease has spread beyond the prostate. Androgen withdrawal remains the only treatment for these men with clinically advanced disease; however, most of these men, who initially respond to hormone ablation therapy, fail and the disease progresses. There is at present no effective treatment for hormone-independent prostate cancer. Several lines of evidence suggest a role of p42/p44 mitogen-activated protein kinase (p42/p44 MAP kinase) signal transduction pathways in prostate cancer. At the molecular level, a variety of genetic alterations lead to an epigenetic mechanism by which a feedback autocrine loop between membrane receptors and associated ligands serves as an essential component of the growth, proliferation, and metastasis of prostate cancer at an advanced and androgen-independent stage. Peptide growth factors are known to exert their effects by a complex array of mechanisms primarily mediated by the p42/p44 MAP kinase signal transduction pathway. Thus, we hypothesized that MAP kinase signal transduction pathways could serve as new and novel targets in prostate cancer therapy. In this article we provide an overview of the role played by MAP kinase signal transduction in the prostate.
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PMID:p42/p44 Mitogen-activated protein kinase signal transduction pathway: a novel target for the treatment of hormone-resistant prostate cancer? 1565 3

The mechanisms that regulate prostate cancer growth and proliferation are not fully understood. IL-6, a multifunctional cytokine, has been shown to play an important role in prostate cancer biology. Functional role of MAP-kinase signal transduction pathways in prostate biology has not been evaluated in detail. In the present study we evaluated the effects of modulation of p42/44 MAP kinase signal transduction pathway on IL-6 expression and secretion by PC3 cells, a line of hormone refractory prostate cancer cells. Results presented, herein, demonstrate that modulation of p42/44 MAP kinase activity results in partial inhibition of synthesis and secretion of IL-6. These data suggest that modulation of p42/p44 may result in regulation of other survival pathways as well.
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PMID:p42/p44 Mitogen-activated protein kinase signal transduction pathway regulates interleukin-6 expression in PC3 cells, a line of hormone-refractory prostate cancer cells. 1565 4

Mutational inactivation or deletion of the phosphatase and tensin homologue deleted on chromosome 10 (PTEN)/MMAC1/TEP gene in human cancer cells leads to a constitutively active status of the phosphatidylinositol 3-kinase/Akt pathway in the cells and has been linked to the lack of responses of the cells to the epidermal growth factor (EGF) receptor-targeted therapeutics. Akt is strongly inhibited by perifosine, an orally active alkyl-lysophospholipid currently being evaluated as an anti-cancer agent in phase 1 and 2 clinical trials. To determine whether perifosine may enhance the antitumor activity of the anti-EGF receptor monoclonal antibody cetuximab/C225 in PTEN-deficient cancer cells, we exposed MDA468 breast cancer cells (which contain mutated PTEN gene) and PC3 prostate cancer cells (in which the PTEN gene is deleted) to perifosine and cetuximab, alone and in combination. Treatment of the cells with perifosine reduced baseline levels of phosphorylated Akt, phosphorylated p44/42 mitogen-activated protein kinase (MAPK) and p38MAPK, and increased baseline levels of phosphorylated stress-activated protein kinase (SAPK)/c-jun NH(2)-terminal kinase (JNK). A 72-h exposure of the MDA468 and PC3 cells to perifosine alone resulted in cell death in a dose-dependent manner, which was enhanced by cetuximab. Addition of subtoxic doses of perifosine to cetuximab treatment also enhanced the cetuximab-induced growth inhibition. The combination treatment enhanced the inhibition of phosphorylation of Akt, p44/42MAPK and p38MAPK, but offset the phosphorylation of SAPK/JNK that was activated by perifosine treatment alone. Taken together, the data showed that perifosine enhances the antitumor activity of cetuximab in PTEN-deficient cancer cells. Further evaluation of the combination treatment in preclinical and clinical studies is warranted.
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PMID:Enhancement of antitumor activity of the anti-EGF receptor monoclonal antibody cetuximab/C225 by perifosine in PTEN-deficient cancer cells. 1617 Mar 46

S100 proteins, a multigenic family of calcium-binding proteins, have been linked to human pathologies in recent years. Deregulated expression of S100 proteins, including S100A8 and S100A9, was reported in association with neoplastic disorders. In a previous study, we identified enhanced expression of S100A8 and S100A9 in human prostate cancer. To investigate potential functional implications of S100A8 and S100A9 in prostate cancer, we examined the influence of over-expressed and of purified recombinant S100A8 and S100A9 proteins in different prostate epithelial cell lines. S100A8 and S100A9 were secreted by prostate cancer cells, a finding which prompted us to analyze a possible function as extracellular ligands. S100A8/A9 induced the activation of NF-kappaB and an increased phosphorylation of p38 and p44/42 MAP kinases. In addition, extracellular S100A8/A9 stimulated migration of benign prostatic cells in vitro. Furthermore, in immunofluorescence experiments, we found a strong speckled co-localization of intracellular S100A8/A9 with RAGE after stimulating cells with recombinant S100A8/A9 protein or by increasing cytosolic Ca2+ levels. In summary, our findings show that S100A8 and S100A9 are linked to the activation of important features of prostate cancer cells.
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PMID:S100A8 and S100A9 activate MAP kinase and NF-kappaB signaling pathways and trigger translocation of RAGE in human prostate cancer cells. 1629 7


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