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)

Constitutively active mitogenic and prosurvival signaling cascades due to aberrant expression and interaction of growth factors and their receptors are well documented in human prostate cancer (PCa). Epidermal growth factor (EGF) and insulin-like growth factor-1 (IGF-1) are potent mitogens that regulate proliferation and survival of PCa cells via autocrine and paracrine loops involving both mitogen-activated protein kinase (MAPK)- and Akt-mediated signaling. Accordingly, here we assessed the effect of inositol hexaphosphate (IP6) on constitutive and ligand (EGF and IGF-1)-induced biological responses and associated signaling cascades in advanced and androgen-independent human PCa PC-3 cells. Treatment of PC-3 cells with 2 mM IP6 strongly inhibited both growth and proliferation and decreased cell viability; similar effects were also observed in other human PCa DU145 and LNCaP cells. IP6 also caused a strong apoptotic death of PC-3 cells together with caspase 3 and PARP cleavage. Mechanistic studies showed that biological effects of IP6 were associated with inhibition of both constitutive and ligand-induced Akt phosphorylation together with a decrease in total Akt levels, but a differential inhibitory effect on MAPKs extra cellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase (JNK1/2), and p38 under constitutive and ligand-activated conditions. Under similar condition, IP6 also inhibited AP-1 DNA-binding activity and decreased nuclear levels of both phospho and total c-Fos and c-Jun. Together, these findings for the first time establish IP6 efficacy in inhibiting aberrant EGF receptor (EGFR) or IGF-1 receptor (IGF-1R) pathway-mediated sustained growth promoting and survival signaling cascades in advanced and androgen-independent human PCa PC-3 cells, which might have translational implications in advanced human PCa control and management.
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PMID:Inositol hexaphosphate downregulates both constitutive and ligand-induced mitogenic and cell survival signaling, and causes caspase-mediated apoptotic death of human prostate carcinoma PC-3 cells. 1954 33

Acacetin (5,7-dihydroxy-4'-methoxyflavone), a flavonoid compound, has anti-peroxidative and anti-inflammatory effects. The effect of acacetin on antimetastasis in human prostate cancer DU-145 cells was investigated. First, the result demonstrated acacetin could exhibit an inhibitory effect on the abilities of the adhesion, invasion, and migration by cell-matrix adhesion assay, wound-healing assay, and Boyden chamber assay. Data also showed acacetin could inhibit the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) involved in the downregulation of the expressions of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and urokinase-type plasminogen activator (u-PA) at both the protein and mRNA levels. Next, acacetin significantly decreased the nuclear levels of nuclear factor kappa B (NF-kappaB), c-Fos, and c-Jun. Also, the treatment with acacetin to DU145 cells also leads to a dose-dependent inhibition on the binding ability of NF-kappaB and activator protein-1 (AP-1). Furthermore, the treatment of inhibitors specific for p38 MAPK (SB203580) to DU145 cells could cause reduced expressions of MMP-2, MMP-9, and u-PA. These results showed acacetin could inhibit the invasion and migration abilities of DU145 cells by reducing MMP-2, MMP-9, and u-PA expressions through suppressing p38 MAPK signaling pathway and inhibiting NF-kappaB- or AP-1-binding activity. These findings proved acacetin might be offered further application as an antimetastatic agent.
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PMID:Acacetin, a flavonoid, inhibits the invasion and migration of human prostate cancer DU145 cells via inactivation of the p38 MAPK signaling pathway. 1969 51

Expression of AP-1 proteins has been associated with a more aggressive clinical outcome in prostate cancer. However, their role and regulation by upstream kinase pathways in response to ionizing radiation has remained elusive. Here, we show that constitutive AP-1 activity in prostate cancer cells is dependent on the activities of EGF-R and PI3K. While inhibition of EGF-R is associated with suppression of c-Jun expression and proliferation, inhibition of PI3K pathway suppresses expression of several AP-1 subunits and proliferation, and also sensitizes prostate cancer cells to gamma-radiation. The importance of AP-1 as a mediator of proliferation and radiation responses is demonstrated by the findings that the expression of JunD, Fra-1 and Fra-2 siRNAs in prostate cancer cells suppress these cellular responses. Together, the findings show that AP-1 activity in prostate cancer cells mediates EGF-R and PI3K signalling, is essential for their proliferation, and confers protection against radiation-induced cell death. Thus, its inhibition would be a lucrative target for therapy in this widely increasing cancer type.
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PMID:Transcription factor AP-1 promotes growth and radioresistance in prostate cancer cells. 1978 73

The c-Jun N-terminal kinase (JNK) has been shown to mediate tamoxifen-induced apoptosis in breast cancer cells. However, the downstream mediators of the JNK pathway linking tamoxifen to effectors of apoptosis have yet to be identified. In this study, we analysed whether c-Jun, the major nuclear target of JNK, has a role in tamoxifen-induced apoptosis of SkBr3 breast cancer cells. We show that before DNA fragmentation and caspase 3/7 activation, cytotoxic concentrations of 4-hydroxytamoxifen (OHT) induced JNK-dependent phosphorylation of c-Jun at JNK sites earlier shown to regulate c-Jun-mediated apoptosis. In addition, OHT induced ERK-dependent expression of c-Fos and transactivation of an AP-1-responsive promoter. In particular, the ectopic expression of dominant-negative constructs blocking either AP-1 activity or c-Jun N-terminal phosphorylation prevented DNA fragmentation after OHT treatment. Furthermore, both c-Fos expression and c-Jun N-terminal phosphorylation preceded OHT-dependent activation of caspase 3-7 in different types of tamoxifen-sensitive cancer cells, but not in OHT-resistant LNCaP prostate cancer cells. Taken together, our results indicate that the c-Jun/c-Fos AP-1 complex has a pro-apoptotic role in OHT-treated cancer cells and suggest that pharmacological boosts of c-Jun activation may be useful in a combination therapy setting to sensitize cancer cells to tamoxifen-mediated cell death.
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PMID:c-Jun activation is required for 4-hydroxytamoxifen-induced cell death in breast cancer cells. 1993 18

We have previously reported that the increase in c-Jun expression induced by quercetin inhibited androgen receptor (AR) transactivation, and Sp1 was involved in quercetin-mediated downregulation of AR activity. Transient transfection assays in this work revealed that co-expression of c-Jun quenched Sp1-induced production of luciferase activity driven by AR promoter or three copies of Sp1 binding elements in the AR promoter. Moreover, c-Jun repressed AR-mediated luciferase activity via androgen-response elements (AREs) of the hK2 gene, while this suppression could be restored partially by cotransfection of Sp1 expression plasmid. The physical associations of c-Jun, Sp1, and AR induced by quercetin were further demonstrated by co-immunoprecipitation experiments. In addition, quercetin-mediated repression of AR expression and activity was partially reversed by blocking of JNK signaling pathway. These results suggested that c-Jun might play an important role in the suppression of AR expression and activity in the presence of quercetin, and association of a c-Jun/Sp1/AR protein complex induced by quercetin represented a novel mechanism that was involved in down-regulation of the AR function in prostate cancer cells.
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PMID:Suppression of the androgen receptor function by quercetin through protein-protein interactions of Sp1, c-Jun, and the androgen receptor in human prostate cancer cells. 2014 54

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potentially useful anticancer agent with exquisite selectivity for cancer cells. Unfortunately, many cancers show or acquire resistance to TRAIL. In this study we report that TRAIL activates a TGF-beta-activated kinase 1 --> mitogen-activated protein kinase (MAPK) kinase 3 (MKK3)/MKK6 --> p38 pathway in prostate cancer cells that transcriptionally upregulates expression of the antiapoptotic BCL-2 family member MCL-1. TRAIL alone triggered robust formation of the 'death-inducing signaling complex' (DISC), activation of the initiator caspase-8, and truncation of the BH3-only protein BID (tBID). Nevertheless, simultaneous disruption of the p38 MAPK pathway was required to suppress MCL-1 expression, thereby allowing tBID to activate the proapoptotic BCL-2 family member BAK and stimulate mitochondrial outer membrane permeabilization (MOMP). Release of the inhibitor-of-apoptosis (IAP) antagonist, Smac/DIABLO, from the intermembrane space was sufficient to promote TRAIL-induced apoptosis, whereas release of cytochrome c and activation of the apoptosome was dispensable. Even after MOMP, however, mitochondrial-generated reactive oxygen species (ROS) activated a secondary signaling pathway, involving c-Jun N-terminal kinases (JNKs), that similarly upregulated MCL-1 expression and partially rescued some cells from death. Thus, stress kinases activated at distinct steps, before and after mitochondrial injury, mediate TRAIL resistance through maintenance of MCL-1 expression.
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PMID:TRAIL-activated stress kinases suppress apoptosis through transcriptional upregulation of MCL-1. 2016 33

Signaling pathways for caspase-2-mediated apoptosis are poorly defined. This is partially due to a lack of a reproducible stimulus to trigger caspase-2 activation. We present the oligonucleotide Dz13, a DNA enzyme that cleaves c-Jun mRNA and is capable of inhibiting various model tumors in mice, which potently induces caspase-2 resulting in apoptosis in a panel of tumor cell lines. Dz13-mediated cell death occurred even in the absence of known caspase-2 molecular partners in p53-induced protein with a death domain, RIP-associated Ich-1/CED homologous protein with death domain, or DNA-dependent protein kinase catalytic subunit, or other caspases in cell lines of breast cancer, prostate cancer, osteosarcoma, and liposarcoma. z-VDVAD-fmk, caspase-2(-/-) mouse embryonic fibroblasts and siRNA silencing of caspase-2 in tumor cells abrogated Dz13-mediated cell death. In an orthotopic tumor model, expression of caspase-2 increased as the tumor metastasized and caspase-2 expression was sporadic in patient tumor specimens. These findings provide hope that Dz13, and other agents that evoke activation of caspase-2, may be therapeutic clinically.
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PMID:Dz13, a c-jun DNAzyme, is a potent inducer of caspase-2 activation. 2018 Jun 31

The DNA enzyme Dz13, targeted against the oncogene c-Jun, is capable of inhibiting various model tumours in mice albeit in ectopic models of neoplasia. In previous studies using orthotopic models of disease, the inhibitory effects of Dz13 on secondary growth was a direct result of growth inhibition at the primary lesion site. Thus, the direct and genuine effects on metastasis were not gauged. In this study, Dz13 was able to inhibit both locoregional and distal metastasis of tumour cells in mice, in studies where the primary tumours were unaffected due to the late and clinically-mimicking nature of treatment commencement. In addition, the effect of Dz13 against tumours has now been extended to encompass breast and prostate cancer. Dz13 upregulated the matrix metalloproteinase (MMP)-2 and MMP-9, and decreased expression of MT1-MMP (MMP-14) in cultured tumour cells. However, in sections of ectopic tumours treated with Dz13, both MMP-2 and MMP-9 were downregulated. Thus, not only is Dz13 able to inhibit tumour growth at the primary site, but also able to decrease the ability of neoplastic cells to metastasize. These findings further highlight the growing potential of Dz13 as an antineoplastic agent.
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PMID:Direct anti-metastatic efficacy by the DNA enzyme Dz13 and downregulated MMP-2, MMP-9 and MT1-MMP in tumours. 2033 87

After glioma pathogenesis-related protein 1 (GLIPR1/Glipr1) was identified, the expression of GLIPR1 was shown to be down-regulated in human prostate cancer, owing in part to methylation in the regulatory region of this gene in prostate cancer cells. Additional studies showed that GLIPR1/Glipr1 expression is induced by DNA-damaging agents independent of p53. Functional analysis of GLIPR1 using in vitro and in vivo gene-transfer approaches revealed both growth suppression and proapoptotic activities for mouse Glipr1 and human GLIPR1 in multiple cancer cell lines. The proapoptotic activities were dependent on production of reactive oxygen species and sustained c-Jun-NH(2) kinase signaling. It was interesting that adenoviral vector-mediated Glipr1 (AdGlipr1) transduction into prostate cancer tissues using an immunocompetent orthotopic mouse model revealed additional biologic activities consistent with tumor-suppressor functions. Significantly reduced tumor-associated angiogenesis and direct suppression of endothelial-cell sprouting activities were documented. In addition, AdGlipr1 strongly stimulated antitumor immune responses that resulted in specific cytotoxic T-lymphocyte activities in this model. Glipr1-related antitumor immunostimulatory activities were confirmed and extended in subsequent studies. Administration of a novel Glipr1 genemodified tumor cell vaccine had significant antitumor activity in a mouse model of recurrent prostate cancer. In conclusion, restoration of GLIPR1 function in prostate cancer cells through GLIPR1 gene-based or GLIPR protein-based delivery methods may provide a safe and effective approach for targeted therapy for a range of malignancies.
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PMID:Glioma pathogenesis-related protein 1: tumor-suppressor activities and therapeutic potential. 2049 10

We recently reported that colored potato extracts and an anthocyanin rich fraction suppressed lymph-node carcinoma of the prostate (LNCaP) and prostate cancer-3 (PC-3) prostate cancer cell proliferation and induced apoptosis via caspase-dependent and caspase-independent pathways. Chlorogenic acid, caffeic acid, gallic acid, catechin, malvidin, and glycoalkaloids (alpha-chaconine and solanine) have now been identified as the major bioactive components of potato, and their effects on LNCaP and PC-3 cell proliferation and apoptosis have been investigated. alpha-chaconine (5 microg/ml) and gallic acid (15 microg/ml) exhibited potent antiproliferative properties and increased cyclin-dependent kinase inhibitor p27 levels in both cell lines. Both alpha-chaconine and gallic acid induced poly [adenosine diphosphate (ADP)] ribose polymerase cleavage and caspase-dependent apoptosis in LNCaP cells; however, caspase-independent apoptosis through nuclear translocation of endonuclease G was observed in both LNCaP and PC-3 cells. alpha-chaconine and gallic acid activated c-Jun N-terminal protein kinase (JNK), and this response played a major role in induction of caspase-dependent apoptosis in LNCaP cells; whereas modulation of JNK and mitogen-activated protein kinase did not affect alpha-chaconine- and gallic acid-induced caspase-independent apoptosis. These results suggest that apoptosis induced by whole potato extracts in prostate cancer cell lines may be in part due to alpha-chaconine and gallic acid.
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PMID:The bioactive compounds alpha-chaconine and gallic acid in potato extracts decrease survival and induce apoptosis in LNCaP and PC3 prostate cancer cells. 2057 21


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