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)

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been reported to induce cell death in a variety of transformed cells but spared the normal cells. In this study, we examined its potential against advanced prostate cancer cells. Treatment of PC-3 and DU145 cells with TRAIL caused a rapid apoptotic cell death, whereas tumor necrosis factor-alpha (TNF-alpha) is ineffective unless in the presence of the protein synthesis inhibitor cycloheximide. The induction of apoptosis by TRAIL in PC-3 cells was mediated by a death receptor, DR 4, and the downstream caspases. Treatment of PC-3 cells with TRAIL also activated c-Jun NH2-terminal kinase 1 (JNK1); however, inhibition of JNK1 activation by its dominant-negative mutant had little effect on TRAIL-induced apoptosis. Furthermore, TRAIL weakly stimulated nuclear factor kappaB activity in PC-3 cells. Interestingly, activation of nuclear factor kappaB pathway by pretreatment with TNF-alpha did not prevent the induction of apoptosis by TRAIL. These data indicate that TRAIL triggers apoptosis in advanced prostate cancer cells through the activation of caspase cascades, which appears to be independent of TNF-alpha- and JNK-mediated mechanisms.
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PMID:Tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in androgen-independent prostate cancer cells. 1081 Nov 14

Tumor necrosis factor superfamily member TRAIL/Apo-2L has recently been shown to induce apoptosis in transformed and cancer cells. Some prostate cancer cells express constitutively active Akt/protein kinase B due to a complete loss of lipid phosphatase PTEN gene, a negative regulator of phosphatidylinositol 3-kinase pathway. Constitutively active Akt promotes cellular survival and resistance to chemotherapy and radiation. We have recently noticed that some human prostate cancer cells are resistant to TRAIL. We therefore examined the intracellular mechanisms of cellular resistance to TRAIL. The cell lines expressing the highest level of constitutively active Akt were more resistant to undergo apoptosis by TRAIL than those expressing the lowest level. Down-regulation of constitutively active Akt by phosphatidylinositol 3-kinase inhibitors, wortmannin and LY294002, reversed cellular resistance to TRAIL. Treatment of resistant cells with cycloheximide (a protein synthesis inhibitor) rendered cells sensitive to TRAIL. Transfecting dominant negative Akt decreased Akt activity and increased TRAIL-induced apoptosis in cells with high Akt activity. Conversely, transfecting constitutively active Akt into cells with low Akt activity increased Akt activity and attenuated TRAIL-induced apoptosis. Inhibition of TRAIL sensitivity occurs at the level of BID cleavage, as caspase-8 activity was not affected. Enforced expression of anti-apoptotic protein Bcl-2 or Bcl-X(L) inhibited TRAIL-induced mitochondrial dysfunction and apoptosis. We therefore identify Akt as a constitutively active kinase that promotes survival of prostate cancer cells and demonstrate that modulation of Akt activity, by pharmacological or genetic approaches, alters the cellular responsiveness to TRAIL. Thus, TRAIL in combination with agents that down-regulate Akt activity can be used to treat prostate cancer.
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PMID:Pro-survival function of Akt/protein kinase B in prostate cancer cells. Relationship with TRAIL resistance. 1224 94

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) has been shown to induce apoptosis in malignant cells without harming normal cells. To determine the antitumor potential of TRAIL against prostate cells, we undertook a comprehensive study that included eight prostate cancer cells lines (CWR22Rv1, Du145, DuPro, JCA-1, LNCaP, PC-3, PPC-1, and TsuPr1) and primary cultures of normal prostate epithelial cells (PrEC). Cells were tested for susceptibility to soluble TRAIL in the presence or absence of the chemotherapeutic agent doxorubicin. TRAIL was also delivered by an adenoviral vector. Our results reveal that Du145, DuPro, LNCap, TsuPr1, and PrEC were resistant to 100 ng/mL TRAIL. JCA-1 and PPC-1 were slightly sensitive (20% killing) and PC-3 and CWR22Rv1 exhibited the highest sensitivity to TRAIL (30% and 50% killing, respectively). The combination of 10 ng/mL TRAIL with doxorubicin resulted in 60-80% cytotoxicity in seven of eight prostate cancer cells. TRAIL-mediated apoptosis involved cleavage of Bid, caspase-3, and PARP, and required caspase-8 and -9 activity. Full-length TRAIL delivered by an adenoviral vector (AdTRAIL-IRES-GFP) killed prostate cancer cell lines and PrEC without requisite doxorubicin cotreatment. Therefore, expression of the transgene from a tissue-specific promotor would make gene therapy with AdTRAIL-IRES-GFP a possibility.
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PMID:Resistance of prostate cancer cells to soluble TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) can be overcome by doxorubicin or adenoviral delivery of full-length TRAIL. 1185 34

A previous study from our laboratory suggested that prostate cancer metastasis to bone may be mediated, in part, by preferential adhesion to human bone marrow endothelial (HBME) cells. Tumor cell adhesion to endothelial cells may be modulated by the effect of cytokines on cell adhesion molecules (CAMs). Tumor necrosis factor-alpha (TNF-alpha) regulates VCAM expression on the endothelium and this effect is enhanced by dihydrotestosterone (DHT). Transforming growth factor-beta (TGF-beta) stimulates the expression of alpha2beta1 integrin on PC-3 cells. The current study investigated the effects of the above cytokines and DHT (singularly and in various combinations) upon HBME and prostate cancer cell expression of VCAM, alpha2 integrin subunit, and beta1 integrin subunit by flow cytometry. We also monitored the effects of the above treatments on PC-3 cell adhesion to HBME monolayers. The data demonstrate that none of the treatments significantly altered the expression of selected CAMs on HBME cell and neoplastic prostate cell lines. The treatment of HBME monolayers with various combinations of cytokines and DHT prior to performing adhesion assays with PC-3 demonstrates that treatments containing TGF-beta reduced PC-3 cell adhesion to HBME monolayers by 32% or greater (P < 0.05). The reduction in PC-3 cell adhesion to TGF-beta-treated HBME monolayers was dose dependent. Interestingly, LNCaP cells but not PC-3 cells treated with TGF-beta had a reduced ability to adhere to untreated HBME monolayers. These results suggest that TGF-beta may reduce tumor cell adhesion to bone marrow microvascular endothelium, in vivo. The biological significance of this observation is discussed.
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PMID:The regulation of prostate cancer cell adhesion to human bone marrow endothelial cell monolayers by androgen dihydrotestosterone and cytokines. 1191 80

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various tumor cells. The anthracycline doxorubicin (DOX) can sensitize several types of cancer cells to TRAIL-mediated apoptosis. Here we report that DOX enhances TRAIL-induced apoptosis and cytotoxicity against prostate cancer cells. Cytotoxicity was determined by a MTT assay. Synergistic effect was assessed by isobolographic analysis. Caspase activity was determined by a quantitative colorimetric assay. The combination treatment with DOX and TRAIL resulted in a synergistic cytotoxic effect on LNCaP, LNCaP-Bcl-2, PC-3, and PC93 human prostate cancer cell lines, but not on normal human prostatic stromal cells. Synergistic cytotoxicity was also obtained even when the exposure time was shortened from 24 to 8 or 2 h. A similar effect was achieved with TRAIL in combination with epirubicin, pirarubicin, or amrubicin. The synergy obtained in cytotoxicity with TRAIL and DOX was also achieved in apoptosis. DOX treatment significantly activated caspase-8, -6, and -3 in LNCaP cells. Furthermore, the synergistic cytotoxicity of TRAIL and DOX was completely inhibited by Z-VAD-FMK, and partly inhibited by Ac-IETD-CHO, Ac-DQTD-CHO, or Ac-DMQD-CHO. These findings indicate that DOX enhances TRAIL-induced apoptosis and cytotoxicity in prostate cancer by activation of caspase cascades, and suggest that TRAIL in combination with DOX have a therapeutic potential in the treatment of prostate cancer.
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PMID:Doxorubicin enhances TRAIL-induced apoptosis in prostate cancer. 1195 88

Tumor necrosis factor-related apoptosis inducing ligand (TRAIL/Apo2L) can induce receptor-mediated apoptosis in prostate cancer cell lines that have been co-treated with the chemotherapeutic agent doxorubicin (Voelkel-Johnson C, et al. Cancer Gene Therapy 2002; 9:164-172). In this study, we report that pretreatment with doxorubicin is sufficient to sensitize cells to TRAIL. To identify possible targets of doxorubicin, we analyzed levels of several Bcl-2 family members, TRAIL receptors and the anti-apoptotic protein c-FLIP. Doxorubicin did not affect steady state levels of Bax, Bcl-2 and Bcl-X(L) in the majority of the prostate cancer cell lines. TRAIL receptor mRNAs (DR4, DR5, and DcR2) were induced by doxorubicin but these changes were not reflected at the protein level. In contrast, in response to doxorubicin, levels of c-FLIP, particularly FLIP(S), decreased in all cell lines tested. The decrease in c-FLIP(S) correlated with onset and magnitude of caspase-8 and PARP cleavage in PC3 cells. In two TRAIL resistant cell lines, DU145 and LNCaP, treatment with TRAIL alone resulted in processing of c-FLIP(L) and initiated abortive caspase-8 proteolysis. TRAIL treatment did not affect levels of c-FLIP(S) in Du145 and LNCaP cells and did not result in PARP cleavage. Therefore, our results suggest that doxorubicin- mediated down regulation of c-FLIP(S) predisposes cells to TRAIL-induced apoptosis.
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PMID:Doxorubicin pretreatment sensitizes prostate cancer cell lines to TRAIL induced apoptosis which correlates with the loss of c-FLIP expression. 1249 82

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in several human tumors both in vitro and in vivo, however, some tumors remain resistant for poorly understood reasons. Using a quantitative DNA fragmentation assay for apoptosis, we have shown that human prostate cancer cells are resistant to a wide range of TRAIL doses up to 500 ng/ml. However, translation inhibitors, such as anisomycin, cycloheximide, emetine, harringtonine, and puromycin, unlike several transcription inhibitors, significantly sensitized PC3-neomycin (PC3-neo) cells to TRAIL-induced apoptosis. These effects were inhibited in PC3 cells engineered to express bcl2 (PC3-bcl2). Translation inhibitors led to activation of c-Jun N-terminal kinase (JNK), which plays a role in this sensitization process because inhibition of JNK activation resulted in protection against TRAIL plus translation inhibitor-induced apoptosis. JNK activation may be required for this process, but it is not sufficient because activation of JNK using an MEKK2 expression vector did not mimic the sensitizing effect of translation inhibitors. Other stress-activated protein kinases, such as ERK and p38, play an insignificant role in determining the apoptotic sensitivity. We conclude that activation of JNK is required for sensitization of PC3 cells to TRAIL-induced apoptosis by translation inhibitors in cells that are otherwise TRAIL-resistant. However, in addition to JNK activation, other aspects of translation inhibition such as the suppressed activity of apoptosis-inhibitory proteins or activation of other signal transduction pathways must also be involved.
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PMID:Translation inhibitors sensitize prostate cancer cells to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by activating c-Jun N-terminal kinase. 1266 65

Prostate cancer is a major health problem among American men and new treatment approaches are needed. Tumor necrosis factor related apoptosis-inducing ligand (TRAIL/Apo2L) is a death ligand that can induce apoptosis in some but not all cancer cells. Resistance to TRAIL-mediated apoptosis can be overcome by radiation or chemotherapy. The effect of doxorubicin/TRAIL combination therapy was compared among PC3, normal prostate epithelial (PrEC) and stromal (PrSC) cells and cell viability measured by MTS assay. Combination of doxorubicin and TRAIL caused cytotoxicity in all cells tested, although PrSC were more resistant. There was no correlation between TRAIL phenotype and expression of c-FLIP, caspases or TRAIL decoy receptors, although PrSC failed to express DR4. A DR4-specific antibody, which behaved as an agonist in combination with doxorubicin, selectively induced cell death in malignant but not normal prostate cells. Although normal PrEC expressed DR4 as determined by western blot, flow cytometry revealed that only maligant prostate cancer cells (PC3, JCA-1) and not PrEC's exhibited DR4 surface expression. Therefore, combination of doxorubicin and an antibody to DR4 might have therapeutic potential for the treatment of prostate cancer by selectively targeting malignant prostate cells.
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PMID:An antibody against DR4 (TRAIL-R1) in combination with doxorubicin selectively kills malignant but not normal prostate cells. 1287 68

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to be selective in the induction of apoptosis in cancer cells with minimal toxicity to normal tissues and this prompted its potential therapeutic application in cancer. However, not all cancers are sensitive to TRAIL-mediated apoptosis and, therefore, TRAIL-resistant cancer cells must be sensitized first to become sensitive to TRAIL. Treatment of prostate cancer (CaP) cell lines (DU145, PC-3, CL-1, and LNCaP) with nitric oxide donors (e.g. (Z)-1-[2-(2-aminoethyl)-N-(2-ammonio-ethyl)amino]diazen-1-ium-1, 2-diolate (DETANONOate)) sensitized CaP cells to TRAIL-induced apoptosis and synergy was achieved. The mechanism by which DETANONOate mediated the sensitization was examined. DETANONOate inhibited the constitutive NF-kappa B activity as assessed by EMSA. Also, p50 was S-nitrosylated by DETANONOate resulting in inhibition of NF-kappa B. Inhibition of NF-kappa B activity by the chemical inhibitor Bay 11-7085, like DETANONOate, sensitized CaP to TRAIL apoptosis. In addition, DETANONOate downregulated the expression of Bcl-2 related gene (Bcl-(xL)) which is under the transcriptional regulation of NF-kappa B. The regulation of NF-kappa B and Bcl-(xL) by DETANONOate was corroborated by the use of Bcl-(xL) and Bcl-x kappa B reporter systems. DETANONOate inhibited luciferase activity in the wild type and had no effect on the mutant cells. Inhibition of NF-kappa B resulted in downregulation of Bcl-(xL) expression and sensitized CaP to TRAIL-induced apoptosis. The role of Bcl-(xL) in the regulation of TRAIL apoptosis was corroborated by inhibiting Bcl-(xL) function by the chemical inhibitor 2-methoxyantimycin A(3) and this resulted in sensitization of the cells to TRAIL apoptosis. Signaling by DETANONOate and TRAIL for apoptosis was examined. DETANONOate altered the mitochondria by inducing membrane depolarization and releasing modest amounts of cytochrome c and Smac/DIABLO in the absence of downstream activation of caspases 9 and 3. However, the combination of DETANONOate and TRAIL resulted in activation of the mitochondrial pathway and activation of caspases 9 and 3, and induction of apoptosis. These findings demonstrate that DETANONOate-mediated sensitization of CaP to TRAIL-induced apoptosis is via inhibition of constitutive NF-kappa B activity and Bcl-(xL) expression.
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PMID:Nitric oxide sensitizes prostate carcinoma cell lines to TRAIL-mediated apoptosis via inactivation of NF-kappa B and inhibition of Bcl-xl expression. 1504 72

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent anti-cancer agent because it induces apoptosis of most tumor cells with little or no effect on normal cells. In this study, we investigated the effect of TRAIL on human prostate normal and cancer cell lines, and found that the prostate cancer cell lines PC-3, ALVA-31, DU 145 and TSU-Pr1 were sensitive to TRAIL-induced apoptosis, while normal PrEC cells and cancer cell line LNCaP were resistant. No correlation was found between the sensitivity of cells to TRAIL and the expression of TRAIL receptors DR4 and DR5, and pro-apoptotic proteins Bax and Bak. However, LNCaP cells displayed a high Akt activity. Furthermore, we found that endothelial nitric oxide synthase (eNOS), one of the Akt substrates, was highly expressed in LNCaP but not in other cells. Inhibition of eNOS activity by NOS inhibitor sensitized LNCaP cells to TRAIL. Moreover, PC-3 cell clones stably expressing eNOS were resistant to TRAIL-induced apoptosis. Taken together, these results indicate that eNOS can regulate the sensitivity of prostate cancer cells to TRAIL, and down-regulation of eNOS activity may sensitize prostate cancer cells to TRAIL-based therapy.
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PMID:eNOS protects prostate cancer cells from TRAIL-induced apoptosis. 1517 22


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