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)

The treatment options available for prostate cancer are limited because of its resistance to therapeutic agents. Thus, a better understanding of the underlying mechanisms of the resistance of prostate cancer will facilitate the discovery of more efficient treatment protocols. Human phosphatidylethanolamine-binding protein 4 (hPEBP4) is recently identified by us as an anti-apoptotic molecule and a potential candidate target for breast cancer treatment. Here we found the expression levels of hPEBP4 were positively correlated with the severity of clinical prostate cancer. Furthermore, hPEBP4 was not expressed in TRAIL-sensitive DU145 prostate cancer cells, but was highly expressed in TRAIL-resistant LNCaP cells, which show highly activated Akt. Interestingly, hPEBP4 overexpression in TRAIL-sensitive DU145 cells promoted Akt activation but inhibited ERK1/2 activation. The hPEBP4-overexpressing DU145 cells became resistant to TRAIL-induced apoptosis consequently, which could be reversed by PI3K inhibitors. In contrast, silencing of hPEBP4 in TRAIL-resistant LNCaP cells inhibited Akt activation but increased ERK1/2 activation, resulting in their sensitivity to TRAIL-induced apoptosis that was restored by the MEK1 inhibitor. Therefore, hPEBP4 expression in prostate cancer can activate Akt and deactivate ERK1/2 signaling, leading to TRAIL resistance. We also demonstrated that hPEBP4-mediated resistance to TRAIL-induced apoptosis occurred downstream of caspase-8 and at the level of BID cleavage via the regulation of Akt and ERK pathways, and that hPEBP4-regulated ERK deactivation was upstream of Akt activation in prostate cancer cells. Considering that hPEBP4 confers cellular resistance to TRAIL-induced apoptosis and is abundantly expressed in poorly differentiated prostate cancer, silencing of hPEBP4 suggests a promising approach for prostate cancer treatment.
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PMID:hPEBP4 resists TRAIL-induced apoptosis of human prostate cancer cells by activating Akt and deactivating ERK1/2 pathways. 3297 31

Transcription factor signal transducer and activator of transcription (Stat)-3 is activated constitutively in prostate cancer (PCA) suggesting that its disruption could be an effective approach to control this malignancy. Here we assessed whether silibinin, a flavanone from Silybum marianum with proven anticancer efficacy in various cancer models, inhibits Stat3 activation in DU145 cells, and if it does, what is the biological fate of the cells? At 50 muM or higher concentrations for 24 or 48 h, silibinin concentration dependently reduced constitutive Stat3 phosphorylation at Tyr705 and Ser727 residues under both serum and serum-starved conditions. Constitutively active Stat3-DNA binding was also inhibited concentration dependently by silibinin; however, apoptotic death together with caspase and poly(ADP-ribose) polymerase (PARP) cleavage was observed by silibinin only under serum-starved conditions suggesting that additional survival pathways are active under serum conditions. In other studies, cells were treated with various specific pharmacological inhibitors where phosphorylation of Stat3 was not reduced by epidermal growth factor receptor and Mitogen activated protein/extracellular signal regulate kinase kinase (MEK1/2) inhibitors, suggesting lack of significant roles of these in Stat3 activation in DU145 cells. Janus kinase (JAK)-1 and JAK2 inhibitors strongly reduced Stat3 phosphorylation but did not result in apoptotic cell death. Interestingly, JAK1 inhibitor only in combination with silibinin resulted in a complete reduction in Stat3 phosphorylation at Tyr705, activated caspase-9 and caspase-3, and caused strong PARP cleavage and apoptotic death of DU145 cells. Given a critical role of Stat3 activation in PCA, our results showed that silibinin inhibits constitutively active Stat3 and induces apoptosis in DU145 cells, and thus might have potential significance in therapeutic intervention of this deadly malignancy.
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PMID:Silibinin inhibits constitutive activation of Stat3, and causes caspase activation and apoptotic death of human prostate carcinoma DU145 cells. 1734 59

It has been reported that genipin, the aglycone of geniposide, induces apoptotic cell death in human hepatoma cells via a NADPH oxidase-reactive oxygen species (ROS)-c-Jun NH(2)-terminal kinase (JNK)-dependent activation of mitochondrial pathway. This continuing work aimed to define that mixed lineage kinase 3 (MLK3) is a key mediator, which connect between ROS and JNK in genipin-induced cell death signaling. In PC3 human prostate cancer cells, genipin stimulated MLK3 activity in concentration- and time-dependent manner. The PC3 cells stably transfected with dominant-negative form of MLK3 was less susceptible to population of the sub-G1 apoptotic cells, activation of caspase, collapse of mitochondrial membrane potential, and release of cytochrome c triggered by genipin, suggesting a crucial role of MLK3 in genipin signaling to apoptotic cell death. Diphenyleneiodonium (DPI), a specific inhibitor of NADPH oxidase, markedly inhibited ROS generation and MLK3 phosphorylation in the genipin-treated cells. Pretreatment with SP0600125, a specific inhibitor of JNK but neither U0126, a specific inhibitor of MEK1/2 nor PD169316, a specific inhibitor of p38 suppressed genipin-induced apoptotic cell death. Notably, both the phosphorylation of JNK and induction of c-Jun induced by genipin were markedly inhibited in PC3-EGFP-MLK3 (K144R) cells expressing a dominant-negative MLK3 mutant. Taken together, our observations suggest genipin signaling to apoptosis of PC3 cells is mediated via activation of ROS-dependent MLK3, which leads to downstream activation of JNK.
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PMID:Mixed lineage kinase 3 connects reactive oxygen species to c-Jun NH2-terminal kinase-induced mitochondrial apoptosis in genipin-treated PC3 human prostate cancer cells. 1770 42

Abnormal intracellular signaling contributes to carcinogenesis and may represent novel therapeutic targets. mitogen/extracellular signal-regulated kinase kinase-5 (MEK5) overexpression is associated with aggressive prostate cancer. In this study, we examined the role of extracellular signal-regulated kinase (ERK5, an MAPK and specific substrate for MEK5) in prostate cancer. ERK5 immunoreactivity was significantly upregulated in high-grade prostate cancer when compared to benign prostatic hyperplasia (P<0.0001). Increased ERK5 cytoplasmic signals correlated closely with Gleason sum score (P<0.0001), bony metastases (P=0.0044) and locally advanced disease at diagnosis (P=0.0023), with a weak association with shorter disease-specific survival (P=0.036). A subgroup of patients showed strong nuclear ERK5 localization, which correlated with poor disease-specific survival and, on multivariant analysis, was an independent prognostic factor (P<0.0001). Analysis of ERK5 expression in matched tumor pairs (before and after hormone relapse, n=26) revealed ERK5 nuclear expression was significantly associated with hormone-insensitive disease (P=0.0078). Similarly, ERK5 protein expression was increased in an androgen-independent LNCaP subline. We obtained the following in vitro and in vivo evidence to support the above expression data: (1) cotransfection of ERK5wt and MEK5D constructs in PC3 cells results in predominant ERK5 nuclear localization, similar to that observed in aggressive clinical disease; (2) ERK5-overexpressing PC3 cells have enhanced proliferative, migrative and invasive capabilities in vitro (P<0.0001), and were dramatically more efficient in forming tumors, with a shorter mean time for tumors to reach a critical volume of 1000 mm(3), in vivo (P<0.0001); (3) the MEK1 inhibitor, PD184352, blocking ERK1/2 activation at low dose, did not suppress proliferation but did significantly decrease proliferation at a higher dose required to inhibit ERK5 activation. Taken together, our results establish the potential importance of ERK5 in aggressive prostate cancer.
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PMID:Aberrant expression of extracellular signal-regulated kinase 5 in human prostate cancer. 1807 19

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

Mutations in the human androgen receptor (AR) gene that lead to C-terminus truncated AR variants are frequently detected in prostate cancer (PC). These AR variants lack both the ligand-binding domain (LBD) and the AF-2 region. The aim of this study was to delineate the alternative mechanisms that lead to the activation of such AR variants as they are unresponsive to hormone stimulation, and to outline consequences of the loss of the LBD/AF-2 region on their functional properties. By using an MMTV-luciferase reporter construct and LY294002, UO126, or ZD1839, inhibitor of PI3K, MEK1/2, and EGFR signaling pathway respectively, we demonstrated that phosphorylation was required for full transcriptional activities of one these AR variants, the Q640X mutant AR. Western-blot analyses confirmed that these inhibitors affect the phosphorylation status of this AR variant. Furthermore, studies of the intranuclear colocalization of the Q640X AR with cofactors, such as CBP, GRIP-1, and c-Jun, reveal that the transcriptional complex that forms around the mutant AR is different to that formed around the wild type AR. We demonstrated that CBP and c-Jun are highly recruited by the mutant AR, and this leads to an unexpected activation of AP-1, NFAT, and NFkappaB transcriptional activities. Similar enhanced activities of these transcription factors were not observed with the wild type AR. The importance of the LBD/AF-2 for the regulation of AR transcriptional activities, the impact of the presence of such AR variants on PC cells proliferation and survival, and on progression to androgen independence are discussed.
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PMID:Specific properties of a C-terminal truncated androgen receptor detected in hormone refractory prostate cancer. 1849 78

Down-regulation of the KAI1 (CD82) metastasis suppressor is common in advanced human cancer, but underlying mechanism(s) regulating KAI1 expression are only now being elucidated. Recent data provide evidence that low levels of KAI1 mRNA in LNCaP cells are caused by binding of beta-catenin/Reptin complexes to a specific motif in the proximal promoter, which prevents binding of Tip60/Pontin activator complexes to the same motif, thus inhibiting transcription. Here, we explored a pathway by which phorbol 12-myristate 13-acetate (PMA) up-regulates KAI1 transcription in LNCaP prostate cancer cells. Pretreatment with specific inhibitors showed that induction of KAI1 by PMA uses classic isoforms of protein kinase C (cPKC), is independent of Ras and Raf, and requires activation of MEK1/2 and ERK1/2, but does not involve p38MAPK. Induction of KAI1 transcription by PMA was associated with enhanced overall acetylation of histones H3 and H4, but only acetylation of H3 was blocked by a PKC inhibitor. Chromatin immunoprecipitation showed that PMA induces recruitment of Tip60/Pontin activator complexes to NFkappaB-p50 motifs in the proximal promoter, and this was blocked by a PKC inhibitor. These changes were not associated with differences in overall levels of Tip60, Pontin, beta-catenin, or Reptin protein expression but with PMA-induced nuclear translocation of Tip60.
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PMID:Phorbol ester enhances KAI1 transcription by recruiting Tip60/Pontin complexes. 1904 21

ERK signaling regulates focal adhesion disassembly during cell movement, and increased ERK signaling frequently contributes to enhanced motility of human tumor cells. We previously found that the ERK scaffold MEK Partner 1 (MP1) is required for focal adhesion disassembly in fibroblasts. Here we test the hypothesis that MP1-dependent ERK signaling regulates motility of DU145 prostate cancer cells. We find that MP1 is required for motility on fibronectin, but not for motility stimulated by serum or EGF. Surprisingly, MP1 appears not to function through its known binding partners MEK1 or PAK1, suggesting the existence of a novel pathway by which MP1 can regulate motility on fibronectin. MP1 may function by regulating the stability or expression of paxillin, a key regulator of motility.
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PMID:Differential requirement for MEK Partner 1 in DU145 prostate cancer cell migration. 1993 Jun 50

SSeCKS/Gravin/AKAP12 ("SSeCKS") encodes a cytoskeletal protein that regulates G(1) --> S progression by scaffolding cyclins, protein kinase C (PKC) and PKA. SSeCKS is down-regulated in many tumor types including prostate, and when re-expressed in MAT-LyLu (MLL) prostate cancer cells, SSeCKS selectively inhibits metastasis by suppressing neovascularization at distal sites, correlating with its ability to down-regulate proangiogenic genes including Vegfa. However, the forced re-expression of VEGF only rescues partial lung metastasis formation. Here, we show that SSeCKS potently inhibits chemotaxis and Matrigel invasion, motility parameters contributing to metastasis formation. SSeCKS suppressed serum-induced activation of the Raf/MEK/ERK pathway, resulting in down-regulation of matrix metalloproteinase-2 expression. In contrast, SSeCKS had no effect on serum-induced phosphorylation of the Src substrate, Shc, in agreement with our previous data that SSeCKS does not inhibit Src kinase activity in cells. Invasiveness and chemotaxis could be restored by the forced expression of constitutively active MEK1, MEK2, ERK1, or PKCalpha. SSeCKS suppressed phorbol ester-induced ERK1/2 activity only if it encoded its PKC binding domain (amino acids 553-900), suggesting that SSeCKS attenuates ERK activation through a direct scaffolding of conventional and/or novel PKC isozymes. Finally, control of MLL invasiveness by SSeCKS is influenced by the actin cytoskeleton: the ability of SSeCKS to inhibit podosome formation is unaffected by cytochalasin D or jasplakinolide, whereas its ability to inhibit MEK1/2 and ERK1/2 activation is nullified by jasplakinolide. Our findings suggest that SSeCKS suppresses metastatic motility by disengaging activated Src and then inhibiting the PKC-Raf/MEK/ERK pathways controlling matrix metalloproteinase-2 expression and podosome formation.
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PMID:SSeCKS/Gravin/AKAP12 inhibits cancer cell invasiveness and chemotaxis by suppressing a protein kinase C- Raf/MEK/ERK pathway. 2001 90

We investigated the effects of testosterone and the pure anti-androgen, bicalutamide, on DNA synthesis and cell cycle in androgen-sensitive or -insensitive human and mouse cell lines by 3H-thymidine incorporation, flow cytometry, RT-PCR and Western blotting. In androgen-dependent mouse SC-3 cells, testosterone induced DNA synthesis, shift of cell cycle distribution from G0/G1 to S/G2/M and expression of cyclin A. The induction was preceded by that of fibroblast growth factor 8 (FGF-8), and completely blocked by monoclonal antibody to FGF-8. Dihydrotestosterone (DHT) induced cyclin A expression in androgen-sensitive human prostate cancer cells, but not in androgen-independent cell lines. Bicalutamide almost completely inhibited these androgen-dependent effects both in LNCaP and SC-3 cells, but had no or limited effect on androgen-independent or FGF-8-induced DNA synthesis, and FGF-8 induced cyclin A expression. Interestingly, bicalutamide inhibited both DNA synthesis and the cyclin A expression in androgen-independent human cell lines in serum-free condition. A MEK1/2 inhibitor U0126 blocked both androgen- and rFGF-8-induced DNA synthesis. Overall, bicalutamide inhibits the cyclin A expression possibly by inhibiting FGF-8 mRNA expression and FGF-8 protein secretion but not by inhibiting FGF receptor (FGFR) signalling in androgen-dependent cell lines, and by other mechanisms in androgen-independent cell lines. The results suggest that combination with compounds such as FGFR signalling inhibitors may provide additional benefits to anti-androgens. It is also suggested that cyclin A could be a sensitive marker for androgen-induced cancer growth and for the growth inhibitory effects of anti-androgen.
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PMID:The pure anti-androgen bicalutamide inhibits cyclin A expression both in androgen-dependent and -independent cell lines. 2012 74


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