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)

Sulindac is the most extensively investigated clinically relevant chemopreventive nonsteroidal anti-inflammatory drug. Sulindac sulfide is one of the major metabolites of sulindac that is believed to mediate its antitumorigenic effects by inducing apoptosis. Recent evidence suggests that sulindac sulfide engages the mitochondrial pathway involving caspase 9 and Bax to mediate its apoptotic effects [Zhang et al., Science (Wash. DC), 290: 989-992, 2000]. In this report, we demonstrate that sulindac sulfide also engaged the membrane death receptor (DR) pathway to mediate apoptosis. Sulindac sulfide up-regulated DR5 and activated the proximal caspase 8 in various different colon and prostate cancer cell lines. Sulindac sulfide specifically up-regulated the DR5 levels but had no effect on the levels of other DRs including DR4, Fas, and tumor necrosis factor receptor 1. To further delineate the role of DR5 in sulindac sulfide-induced apoptosis, we used JCA-1 prostate cancer cells that are deficient in mounting a Fas and tumor necrosis factor receptor 1-dependent apoptotic response but are proficient in mediating DR5-dependent apoptosis. JCA-1 cells were stably transfected with dominant-negative Fas-associated death domain to block the flow of apoptotic signals originating from the endogenous DR5, and sulindac sulfide-induced apoptosis was investigated. Our results indicated that by blocking the DR5-dependent apoptotic pathway, dominant-negative Fas-associated death domain did indeed inhibit sulindac sulfide-induced apoptosis. Furthermore, exogenous tumor necrosis factor-related apoptosis-inducing ligand, the ligand for DR5, also potentiated sulindac sulfide-induced apoptosis in all of the cell lines tested, thereby further supporting the involvement of DR5 in sulindac sulfide-induced apoptosis. Thus, our results demonstrate that sulindac sulfide also engages the membrane DR pathway involving DR5 and proximal caspase 8 to induce apoptosis.
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PMID:Sulindac sulfide-induced apoptosis involves death receptor 5 and the caspase 8-dependent pathway in human colon and prostate cancer cells. 1155 70

Prostate cancer cells are generally resistant to apoptosis by conventional therapy. During a search for molecules that may overcome prostate cancer cell survival mechanisms, we identified the prostate apoptosis response-4 (Par-4) gene. Par-4 induced apoptosis of selective prostate cancer cells PC-3, DU-145, and TSU-Pr and caused tumor regression by inhibition of NF-kappaB activity and cell membrane trafficking of Fas and FasL that leads to the activation of the Fas-Fas-associated death domain-caspase-8 pro-death pathway. Neither Fas pathway activation alone nor inhibition of NF-kappaB activity with IkappaB-super repressor was sufficient to induce apoptosis of prostate cancer cells. Coregulation of these two pathways was essential and sufficient for Par-4 to induce apoptosis. On the other hand, prostate cancer cells LNCaP or normal prostatic epithelial cells that were resistant to apoptosis by Par-4 did not show Fas or FasL trafficking. These findings identify a mechanism of apoptosis by Par-4 and suggest that Par-4 may have therapeutic potential.
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PMID:Par-4 drives trafficking and activation of Fas and Fasl to induce prostate cancer cell apoptosis and tumor regression. 1158 63

The tumor necrosis factor (TNF) receptor family are ligand-regulated transmembrane proteins that mediate apoptosis as well as activation of the transcription factor NF-kappaB. Exogenous expression of DR6, a recently identified member of the TNF receptor family, induced apoptosis in untransformed or tumor-derived cells and the apoptotic function of DR6 was inhibited by co-expression of Bcl-2, Bcl-x(L) or the inhibitor-of-apoptosis (IAP) family member, survivin. Expression of a dominant negative mutant of FADD failed to protect from DR6-mediated apoptosis indicating that unlike TNFR1 and Fas, DR6 induced apoptosis via a FADD-independent mechanism. Despite the ability of exogenous DR6 expression to induce apoptosis, DR6 mRNA and protein were found to be elevated in prostate tumor cell lines and in advanced stages of prostate cancer. Analysis of several anti-apoptotic proteins revealed that Bcl-x(L) levels and serine 32 phosphorylation of IkappaB, the natural inhibitor of NF-kappaB, were similarly elevated in cells expressing high levels of DR6, suggesting that NF-kappaB-regulated survival proteins may protect from DR6-induced apoptosis and that DR6 is a target of NF-kappaB regulation. Treatment of LnCAP cells with TNF-alpha resulted in increases in both DR6 mRNA and protein levels, and this induction was suppressed by inhibitors of NF-kappaB. Similarly, treatment of cells expressing high levels of DR6 with indomethacin and ibuprofen, compounds also known to perturb NF-kappaB function, resulted in a dose-dependent decrease in DR6 protein and mRNA levels. These results demonstrate that TNF-alpha signaling induces the expression of a member of its own receptor family through activation of NF-kappaB.
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PMID:Tumor necrosis factor-alpha induces the expression of DR6, a member of the TNF receptor family, through activation of NF-kappaB. 1175 79

The cytotoxic efficacy and kinetics involved in sensitization of Apo2L/TRAIL-resistant, androgen-independent prostate cancer cells to Apo2L/TRAIL or tumor necrosis factor-alpha or Fas ligand-mediated apoptosis were tested using subclinical concentrations of actinomycin D, paclitaxel, cisplatinum, gemcitabine, and radiation in CL-1, LNCaP, DU-145, and PC3 prostate cancer cell lines. CL-1 cells expressed all four Apo2L/TRAIL receptors and were resistant to Apo2L/TRAIL-mediated apoptosis (1-5,000 ng/mL) and to the sensitizers when given alone. Pretreatment with actinomycin D followed by Apo2L/TRAIL or tumor necrosis factor-alpha or anti-Fas CH-11 monoclonal antibody, but not in the reverse order, induced apoptosis in all cell lines. Synergistic sensitization in CL-1 cells was shown also with gemcitabine but not with cisplatinum, VP-16, paclitaxel, or radiation. Incubating the Apo2L/TRAIL-resistant CL-1, LNCaP, DU-145, and PC3 cell lines with 100 ng/mL actinomycin D for 4 hours followed by Apo2L/TRAIL for 24 hours resulted in 45.4 +/- 10.3%, 58.8 +/- 3.6%, 53.4 +/- 1.4%, and 84.2 +/- 8.4% apoptosis, respectively. Prolonging the sensitization time to 24 hours followed by 20 hours of incubation with Apo2L/TRAIL further enhanced the killing activity against CL-1 cells to 89 +/- 1% (delta = 60%, synergistic ratio = 3.1). This killing has a biphasic pattern that was contributed to by apoptosis (83%) and necrosis (17%) at 10 hours (peak) and 40% and 60%, respectively, at 20 hours. These results suggest that prostate cancer cells' resistance to Apo2L/TRAIL-mediated apoptosis can be reversed and synergy is achieved by sensitization of tumor cells with subclinical concentrations of actinomycin D or gemcitabine and may be useful clinically for the treatment of metastatic hormone- and drug-refractory prostate cancer.
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PMID:Actinomycin D and gemcitabine synergistically sensitize androgen-independent prostate cancer cells to Apo2L/TRAIL-mediated apoptosis. 1175 69

The PTEN tumor suppressor is frequently mutated in human tumors. Loss of PTEN function is associated with constitutive survival signaling through the phosphatidylinositol-3 kinase/Akt pathway. Therefore, we asked if reconstitution of PTEN function would lead to the reversal of resistance to apoptosis in prostate cancer cells. Adenovirus-mediated expression of PTEN completely suppressed constitutive Akt activation in LNCaP prostate cancer cells and enhanced apoptosis induced by a broad range of apoptotic stimuli. PTEN expression sensitized cells to death receptor-mediated apoptosis induced by tumor necrosis factor, anti-Fas antibody, and TRAIL. PTEN also sensitized cells to non-receptor mediated apoptosis induced by a kinase inhibitor staurosporine and chemotherapeutic agents mitoxantrone and etoposide. PTEN-mediated apoptosis was accompanied by caspase-3 and caspase-8 activation and was inhibited by a broad specificity caspase inhibitor Z-VAD-fmk. Bcl-2 overexpression also blocked PTEN-mediated apoptosis. Lipid phosphatase activity of PTEN is required for apoptosis as the PTEN G129E mutant selectively deficient in lipid phosphatase activity was unable to sensitize cells to apoptosis. PTEN-mediated apoptosis involves a FADD-dependent pathway for both death receptor-mediated and drug-induced apoptosis as coexpression of a dominant negative FADD mutant blocked PTEN-mediated apoptosis. Since in death receptor signaling, FADD mediates activation of caspase-8, which in turn cleaves BID, and since caspase-8 is activated in PTEN-mediated apoptosis, we examined BID cleavage in PTEN-mediated apoptosis. PTEN facilitated BID cleavage after treatment with low doses of staurosporine and mitoxantrone. BID cleavage was inhibited by dominant negative FADD. Taken together, these data are consistent with the hypothesis that PTEN promotes drug-induced apoptosis by facilitating caspase-8 activation and BID cleavage through a FADD-dependent pathway.
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PMID:PTEN sensitizes prostate cancer cells to death receptor-mediated and drug-induced apoptosis through a FADD-dependent pathway. 1180 75

To evaluate the clinical usefulness of measuring serum soluble Fas (sFas) for differentiation between prostate cancer and benign prostate hyperplasia (BPH) and for staging of prostate cancer, serum sFas and PSA were determined in 38 and 20 men with prostate cancer and BPH, respectively, before treatment. In 17 patients, sFas and PSA were measured one hour after transrectal ultrasound-guided sextant biopsy in order to examine the leakage of sFas into the circulation after prostatic injury. Patients with prostate cancer had a significantly higher level of sFas than those with BPH. The serum sFas level was statistically elevated in patients with metastatic prostate cancer. There was a statistically significant correlation between sFas and PSA in patients with prostate cancer but not in those without cancer. The serum sFas did not change one hour after systematic prostatic biopsy although PSA levels were markedly elevated. sFas levels might be useful as a discriminator between prostate cancer and BPH while sFas might indicate the tumor burden in patients with prostate cancer.
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PMID:Serum soluble Fas level for detection and staging of prostate cancer. 1184 29

To enhance the NK population induced by Herpes Simplex virus thymidine kinase (HSV-tk) gene transduction and ganciclovir (GCV) treatment, adenovirus-mediated (Ad) expression of IL-12 was added to Ad.HSV-tk + GCV as combination gene therapy. This approach resulted in improved local and systemic growth suppression in a metastatic model of mouse prostate cancer (RM-1). In vitro assay of tumor infiltrating lymphocytes noted superior lysis of both RM-1 and Yac-1 targets with combination therapy, but in vivo depletion of NK cells only negatively impacted on systemic growth inhibition. TUNEL assay of primary tumors noted induction of apoptosis between two and four times higher than controls lasting for 6-8 days post-vector injection. After demonstrating that Ad.HSV-tk/GCV and Ad.mIL-12-induced IFN-gamma independently up-regulated expression of FasL and Fas, respectively, studies examined tumor cell-mediated death through Fas/FasL-induced apoptosis as a mechanism of primary tumor growth suppression. In vitro, combination therapy at low vector doses resulted in synergistic growth suppression, which could be negated by the addition of anti-FasL antibody. In vivo co-inoculation of an adenovirus expressing soluble Fas resulted in combination therapy-treated tumors, which were three times larger than expected, and a reduction in apoptosis to baseline levels. In FasL knockout mice, combination therapy maintained the superior results experienced in wild-type mice, indicating that tumor cell, not host cell FasL, was responsible for Fas transactivation. Therefore, the combination of Ad.HSV-tk/GCV + Ad.mIL-12 results in enhanced local growth control via apoptosis due to tumor cell expression of Fas and FasL and improved anti-metastatic activity secondary to a strong NK response.
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PMID:A novel bystander effect involving tumor cell-derived Fas and FasL interactions following Ad.HSV-tk and Ad.mIL-12 gene therapies in experimental prostate cancer. 1194 76

Prostate cancer is the second leading cause of cancer death in the United States. Treatment options for confined disease are generally successful in prolonging life but long-term cures (10-15 years) are elusive for the majority of patients. The prognosis for advanced extra-capsular prostate cancer is grim. However, we are now entering the era of gene therapy options for treatment of prostate cancer. The human genome project coupled with genomics and protemics are providing information that will lead to selection of genes for treatment of prostate cancer. The problem is the science of delivery lags behind knowledge of gene function. Thus, it is important to develop therapies that do not require delivery to 100% of tumor cells but which nevertheless kills the entire cancer by virtue of the bystander effect or other means. This review covers the use, in gene therapy, of apoptotic inducing molecules such as Fas Ligand, and TRAIL which are believed to induce bystander killing activity and Bax which also may function in a similar way.
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PMID:The use of Fas Ligand, TRAIL and Bax in gene therapy of prostate cancer. 1210 35

The aim of this study was to examine the effect of two of the most commonly used viral vectors, that is, retrovirus and adenovirus, on the antigen presentation of dendritic cells (DCs). DCs were generated from CD34(+) hematopoietic precursors and CD14(+) monocytes of the same prostate cancer patients. Adenoviral transduction of monocyte-derived DCs (MO-DCs) resulted in upregulation of CD80, CD86, and CD83 expression. Adenovirus-transduced MO-DCs were also more potent stimulators of allogeneic lymphocytes, produced increased amounts of the cytokines tumor necrosis factor alpha and interleukin 12 p70, and exhibited increased expression of NF-kappaB and antiapoptotic molecules Bcl-X(L) and Bcl-2. Enhanced expression of the antiapoptotic molecules correlated with increased resistance of adenovirus-transduced MO-DCs to spontaneous as well as Fas-mediated cell death. In contrast to the adenoviral construct, no significant transduction of MO-DCs with the retrovirus could be obtained. Transduction of CD34(+) cell-derived DCs with the retrovirus or the adenovirus did not significantly alter expression of the costimulatory molecules or cytokines studied. At lower stimulation ratios, CD34(+) cell-derived DCs transduced with retrovirus were less potent in their ability to stimulate allogeneic lymphocytes in comparison with nontransduced DCs. Our results indicate that adenoviral vectors may be more suitable for gene delivery to DCs for immunotherapy.
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PMID:Recombinant adenovirus vector activates and protects human monocyte-derived dendritic cells from apoptosis. 1222 9

Fas-associated death domain (FADD) plays an important role as an adapter molecule in Fas (CD95/APO-1)-mediated apoptosis and contributes to anticancer drug-induced cytotoxicity. We treated three human prostate cancer cell lines with etoposide, a toposiomerase II inhibitor with activity against various tumors including prostate cancer. We found that the overexpression of FADD sensitizes etoposide-induced apoptosis through a rapid activation of c-Jun NH(2)-terminal kinase (JNK) and, subsequently, of caspase 3. In addition, phosphorylation of FADD at serine 194 coincided with this sensitization. Treatment with the caspase 3 inhibitor, N-acetyl-Asp-Glu-Val-Asp-aldehyde (DEVD-CHO), or overexpression of either mitogen-activated protein kinase kinase (MKK) 7 or Bcl-xL canceled FADD-mediated sensitization to etoposide-induced apoptosis. Moreover, treatment with the caspase 8 inhibitor, benzyloxy-carbonyl-Val-Ala-Asp-fluoromethylketone (z-IETD-fmk), or overexpression of viral FLICE/caspase-8-inhibitory protein (FLIP) from equine herpesvirus type 2 E8 also had an inhibitory effect, supporting a major involvement of a caspase 8-dependent mitochondrial pathway. Interestingly, FADD was phosphorylated, and etoposide-induced JNK/caspase activation and apoptosis were enhanced in the cells arrested at G2/M transition, but not in those overexpressing mutant FADD, in which 194 serine was replaced by alanine. Our results demonstrate that phosphorylated FADD-dependent activation of the JNK/caspase pathway plays a pivotal role in sensitization to etoposide-induced apoptosis in prostate cancer cells.
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PMID:Phosphorylation of Fas-associated death domain contributes to enhancement of etoposide-induced apoptosis in prostate cancer cells. 1241 47


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