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)

Activation of the PI3K/Akt signaling cascade is often associated with advanced forms of prostatic carcinoma (CaP). This is likely explained by the common loss of the PTEN gene in a majority of CaP patients. Conversely, activation of the Raf/MEK/ERK pathway is seldom linked with prostatic disease. The interplay between these two pathways in advanced CaP has not been established. The following manuscript demonstrates that Akt can directly associate with Raf-1 causing its inactivation via phosphorylation of a negative regulatory residue (serine 259). Inhibition of PI3K with either LY294002 and wortmannin was sufficient to cause upregulation of ERK activity as measured by immunoblotting. Prolonged treatment with two commonly-used chemotoxic compounds, doxorubicin and paclitaxel, caused increased activation of ERK in PTEN-positive DU145 cells, but not PTEN-negative PC3 cells. Others have reported that ERK activation is essential for drug-induced death, which, when combined with these data, supports the notion that Akt plays an integral role in the response of prostate cancer cells to chemotherapeutic drugs. These results demonstrate that, in prostate cancer cells, the efficacy of chemotherapy may be limited by its effects on the intracellular signaling pathways found within the cell. The genotype of the tumor must be considered for an effective response to these and other antineoplastic drugs.
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PMID:Akt inactivates ERK causing decreased response to chemotherapeutic drugs in advanced CaP cells. 1825 41

Adhesion is a hallmark of haematological and solid cancer cells. All five classes of cell adhesion molecules (CAM) - integrins, cadherins, immunoglobulin-like CAMs, selectins and CD44s - are characteristically dysregulated in human cancer. Adhesion enables and promotes cancer-defining biological processes like growth, survival, migration, extravasation, homing, and metastasis. Furthermore, cell adhesion mediates drug resistance (CAM-DR) in multiple myeloma, malignant lymphoma, acute and chronic leukaemias, as well as in pancreatic cancer, neuroblastoma, small cell and non-small cell lung cancer, mesothelioma, colorectal carcinoma, and breast cancer. Cell adhesion protects from death by radiation, genotoxic chemotherapy, or targeted pathway inhibitors. Adhesion molecules are overexpressed on drug resistant cells (e.g. multiple myeloma or prostate cancer). Very recently, several cell adhesion mediated survival pathways have been elucidated, with key mediators being LFA-1, VLA-4, FAK, ILK, Src, PI3K, Akt, Ras, MEK, Erk, HMG-CoA reductase, Rho, Rho kinase, PKC, and NFkB. Because the surface and the intracellular targets are now known and because specific compounds are becoming increasingly available, first clinical trials regarding ANTI-ADHESION therapies are ongoing. However, in comparison to the comprehensive preclinical and clinical knowledge about CAMs, the number of drugs developed thusfar is quite low. ANTI-ADHESION strategies include targeting of surface antigens, inhibition of cell adhesion associated pathways, inhibition of CAM-DR, and targeted drug delivery. As ANTI-ADHESION is based on general characteristics of cancer cells independent of specific disease entities or treatment modalities, it may become a successful, low-toxic and broadly applicable concept in cancer treatment.
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PMID:ANTI-ADHESION evolves to a promising therapeutic concept in oncology. 1839 55

NAG-1 (nonsteroidal anti-inflammatory drug-activated gene), a member of the transforming growth factor-beta superfamily, is involved in many cellular processes, such as inflammation, apoptosis/survival, and tumorigenesis. Vitamin E succinate (VES) is the succinate derivative of alpha-tocopherol and has antitumorigenic activity in a variety of cell culture and animal models. In the current study, the regulation and role of NAG-1 expression in PC-3 human prostate carcinoma cells by VES was examined. VES treatment induced growth arrest and apoptosis as well as an increase in NAG-1 protein and mRNA levels in a time- and concentration-dependent manner. VES treatment induced nuclear translocation and activation of p38 kinase. Pretreatment with p38 kinase inhibitor blocked the VES-induced increase in NAG-1 protein and mRNA levels, whereas an inhibition of protein kinase C, Akt, c-Jun NH(2)-terminal kinase, or MEK activity had no effect on VES-induced NAG-1 levels. Forced expression of constitutively active MKK6, an upstream kinase for p38, induced an increase in NAG-1 promoter activity, whereas p38 kinase inhibitor blocked MKK6-induced increase in NAG-1 promoter activity. VES treatment resulted in >3-fold increase in the half-life of NAG-1 mRNA in a p38 kinase-dependent manner and transient transfection experiment showed that VES stabilizes NAG-1 mRNA through AU-rich elements in 3'-untranslated region of NAG-1 mRNA. The inhibition of NAG-1 expression by small interfering RNA significantly blocked VES-induced poly(ADP-ribose) polymerase cleavage, suggesting that NAG-1 may play an important role in VES-induced apoptosis. These results indicate that VES-induced expression of NAG-1 mRNA/protein is regulated by transcriptional/post-transcriptional mechanism in a p38 kinase-dependent manner and NAG-1 can be chemopreventive/therapeutic target in prostate cancer.
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PMID:Vitamin E succinate induces NAG-1 expression in a p38 kinase-dependent mechanism. 1841 10

Androgen receptor (AR) signalling plays a pivotal role in prostate cancer pathogenesis and progression. However, androgen-mediated AR signalling is yet to be fully understood. EGFR and MAP kinase signalling pathways play predominant roles in AR function. Therefore, we investigated the interaction of EGFR signalling and AR activity in AR-positive LNCaP cells. We found that 5alpha-dihydrotestosterone (DHT) and EGF had a synergistic effect on AR activity as detected by a luciferase reporter system, although EGF alone did not activate AR. Both ERK1/2 and p38 were involved in DHT and DHT/EGF-induced AR activation as detected by specific MEK and p38 inhibitors. Furthermore, 24-h treatment of the cells with DHT resulted in ubiquitination and down-regulation of the EGFR. This effect could be inhibited by the anti-androgen flutamide, suggesting an androgen-dependent mechanism. On the other hand, DHT-treatment strongly increased AR levels in LNCaP cells. These data suggest a complex regulatory loop between activated AR and EGFR. In conclusion, activation of AR by both DHT and EGF/DHT involves the MAP kinase pathway. Long-term activation of AR results in increase of AR levels, which through so far unknown regulatory mechanisms results in ubiquitination and degradation of the EGFR.
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PMID:Dihydrotestosterone interacts with EGFR/MAPK signalling and modulates EGFR levels in androgen receptor-positive LNCaP prostate cancer cells. 1869 94

TNFalpha exerts apoptosis throughout an intracellular transduction pathway that involves the kinase proteins TRAF-2 (integration point of apoptotic and survival signals), ASK1 (pro-apoptotic protein), MEK-4 (p38 activator and metastasis suppressor gene), JNK (stress mitogen activated protein kinase) and the transcription factor AP-1. TNFalpha also exerts proliferation by p38 activation, or when TRAF-2 simultaneously induces the transcription factor NF-kappaB by NIK. NIK and p38 may also be activated by IL-1. P38 activated several transcription factors such as Elk-1, ATF-2 and NF-kappaB. NIK also may activate NF-kappaB. The aim of the present article was to evaluate the different components of this TNFalpha/IL-1 transduction pathway in human prostate carcinoma (PC) in comparison with normal human prostate. In prostate cancer, pro-apoptotic TNFalpha/AP-1 pathway is probably inactivated by different factors such as p21 (at ASK-1 level) and bcl-2 (at JNK level), or diverted towards p38 or NIK activation. IL-1alpha enhances proliferation through IL-1RI that activates either NIK or p38 transduction pathway. P38 and NIK activate different transcription factors related with cell proliferation and survival such as ATF-2, Elk-1 or NF-kappaB. In order to search a possible target to cancer prostate treatment we proposed that inhibition of several proinflamatory cytokines such as IL-1 and TNFalpha might be a possible target for PC treatment, because decrease the activity of all transduction pathway members that activate transcription factors as NF-kappaB, Elk-1 or ATF-2.
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PMID:TNF-alpha/IL-1/NF-kappaB transduction pathway in human cancer prostate. 1871 80

The AKT/mammalian target of rapamycin (AKT/mTOR) and ERK MAPK signaling pathways have been shown to cooperate in prostate cancer progression and the transition to androgen-independent disease. We have now tested the effects of combinatorial inhibition of these pathways on prostate tumorigenicity by performing preclinical studies using a genetically engineered mouse model of prostate cancer. We report here that combination therapy using rapamycin, an inhibitor of mTOR, and PD0325901, an inhibitor of MAPK kinase 1 (MEK; the kinase directly upstream of ERK), inhibited cell growth in cultured prostate cancer cell lines and tumor growth particularly for androgen-independent prostate tumors in the mouse model. We further showed that such inhibition leads to inhibition of proliferation and upregulated expression of the apoptotic regulator Bcl-2-interacting mediator of cell death (Bim). Furthermore, analyses of human prostate cancer tissue microarrays demonstrated that AKT/mTOR and ERK MAPK signaling pathways are often coordinately deregulated during prostate cancer progression in humans. We therefore propose that combination therapy targeting AKT/mTOR and ERK MAPK signaling pathways may be an effective treatment for patients with advanced prostate cancer, in particular those with hormone-refractory disease.
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PMID:Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model. 1872 93

Overexpression of focal adhesion kinase (FAK) has been well correlated with tumor development and/or the maintenance of tumor phenotype. In addition, inappropriate activation of the extracellular regulated kinase (ERK) signaling pathway is common to many human cancers. In the present study, we investigated the interplay between FAK and ERK in androgen-independent prostate cancer cells (PC3 and DU145 cells). We observed that suppression of FAK expression using small interfering RNA-mediated knockdown decreased the clonogenic activity, whereas overexpression of FAK increased it. We also observed that detachment of PC3 and DU145 cells from their substrate induced tyrosine phosphorylation of FAK. ERK knockdown diminished FAK protein levels and tyrosine phosphorylation of FAK as well as FAK promoter-reporter activity. We also tested the effect of MEK inhibitors and small interfering RNA-mediated knockdown of ERK1 and/or ERK2 on cell proliferation, invasiveness, and growth in soft agar of PC3 and DU145 cells. Inhibition of ERK signaling grossly impaired clonogenicity as well as invasion through Matrigel. However, inhibition of ERK signaling resulted in only a modest inhibition of 3H-thymidine incorporation and no effect on overall viability of the cells or increased sensitivity to anoikis. Taken together, these data show, for the first time, a requirement for FAK in aggressive phenotype of prostate cancer cells; reveal interdependence of FAK and ERK1/2 for clonogenic and invasive activity of androgen-independent prostate cancer cells; suggest a role for ERK regulation of FAK in substrate-dependent survival; and show for the first time, in any cell type, the regulation of FAK expression by ERK signaling pathway.
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PMID:Focal adhesion kinase controls aggressive phenotype of androgen-independent prostate cancer. 1892 79

Recent evidence suggests tumor-initating cells (TICs), also called cancer stem cells, are responsible for tumor initiation and progression; therefore, they represent an important cell population for development of future anti-cancer therapies. In this study, we show that the sesquiterpene lactone parthenolide (PTL) is cytotoxic to prostate TICs isolated from prostate cancer cell lines: DU145, PC3, VCAP, and LAPC4, as well as primary prostate TICs. Furthermore, PTL inhibited TIC-driven tumor formation in mouse xenografts. Using an integrated molecular profiling approach encompassing proteomics, profiles of activated transcription factors and genomics we ascertained the effects of PTL on prostate cancer cells. In addition to the previously described effects of PTL, we determined that the non-receptor tyrosine kinase src, and many src signaling components, including: Csk, FAK, beta1-arrestin, FGFR2, PKC, MEK/MAPK, CaMK, ELK-1, and ELK-1-dependent genes are novel targets of PTL action. Furthermore, PTL altered the binding of transcription factors important in prostate cancer including: C/EBP-alpha, fos related antigen-1 (FRA-1), HOXA-4, c-MYB, SNAIL, SP1, serum response factor (SRF), STAT3, X-box binding protein-1 (XBP1), and p53. In summary, we show PTL is cytotoxic to prostate TICs and describe the molecular events of PTL-mediated cytotoxicity. Therefore, PTL represents a promising therapeutic for prostate cancer treatment.
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PMID:Effects of the sesquiterpene lactone parthenolide on prostate tumor-initiating cells: An integrated molecular profiling approach. 1920 13

Prostate cancer is one of the most prominent malignancies of elderly males. The growth of normal prostate and prostate cancer (PCa) cells depend on functional androgen receptor (AR), a ligand controlled transcription factor and member of the nuclear receptor superfamily. Binding of agonistic ligand enhances the transactivation function of AR and hence promotes the growth of prostate epithelial cells. We have earlier shown that AR antagonistic ligands such as cyproterone acetate (CPA) promote the recruitment of transcriptional corepressors such as silencing mediator of retinoid and thyroid receptor (SMRT) leading to repression of AR transactivation in non-PCa cells. Unfortunately, however, in LNCaP PCa cells, CPA functions as an agonist and thereby increases AR transactivation function. Here, we show that activated MEK signaling cascade inhibits functional recruitment of corepressor SMRT to CPA-bound AR in PCa cells. Chemical blockade of MEK kinase using a specific inhibitor U0126 increases the interaction and hence repression of AR by the corepressor SMRT in LNCaP PCa cells. This inhibition also results in enhanced antagonistic behavior of CPA as assessed by reporter and cell-growth assays. Moreover, the growth of LNCaP cells stably overexpressing SMRT was more robustly inhibited in the presence of CPA and U1026. In line with this, the growth rate of LNCaP cells was decelerated in the presence of both CPA and U0126. This suggests that activated MEK signaling pathway attenuates the functional recruitment of corepressor SMRT to AR induced by antagonists and thus indicates the important role of corepressors in mediating repression of both AR transactivation and PCa cell growth by antagonists. Furthermore, these findings suggest that combining receptor antagonists with signaling inhibitors could be a beneficial approach for PCa treatment.
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PMID:Inhibition of MAPK-signaling pathway promotes the interaction of the corepressor SMRT with the human androgen receptor and mediates repression of prostate cancer cell growth in the presence of antiandrogens. 1922 55

Enhanced RAS signaling and decreased androgen dependence of prostate cancer cells accompany poor clinical outcomes. Elevated autocrine fibroblast growth factors 2 (FGF-2) signaling promotes prostate cancer cell growth and survival. Expression of lysyl oxidase (LOX) inhibits RAS transforming activity. LOX is secreted as 50 kDa pro-LOX protein and then undergoes extracellular proteolytic processing to form approximately 30 kDa LOX enzyme and approximately 18 kDa propeptide (LOX-PP). We have previously shown that LOX-PP inhibits breast cancer cell transformation and tumor formation, but mechanisms of action of LOX-PP have not been fully elucidated. Here we report that LOX expression is reduced in prostate cancer cell lines and that recombinant LOX-PP protein inhibits serum-stimulated DNA synthesis and MEK/ERK and PI3K/AKT pathways in DU 145 and PC-3 androgen-independent cell lines. In DU 145 cells, treatment with a pharmacologic FGF-receptor inhibitor or a neutralizing anti-FGFR1 antibody mimicked LOX-PP inhibition of serum-stimulated DNA synthesis. FGF-2-stimulated DNA synthesis, ERK1/2, AKT and FRS2alpha activation were found all to be inhibited by LOX-PP in DU 145 cells. LOX-PP reduced specific binding of FGF-2 to DU 145 cells, suggesting that LOX-PP targets FGF signaling at the receptor. Interestingly, PC-3 cells did not respond to FGF-2, consistent with previous reports. We conclude that LOX-PP inhibits proliferation of DU 145 cells by interfering with FGFR(s) binding and signaling, and that LOX-PP has other mechanisms of action in PC-3 cells.
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PMID:Lysyl oxidase propeptide inhibits prostate cancer cell growth by mechanisms that target FGF-2-cell binding and signaling. 1959 71


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