Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

LNCaP prostate cancer cells are highly resistant to induction of programmed cell death by y-irradiation and somewhat sensitive to the death-inducing effects of tumor necrosis factor (TNF)-alpha. Simultaneous exposure of LNCaP cells to TNF-alpha and 8 Gy of irradiation was synergistic and resulted in a 3-fold increase of apoptotic cells within 72 h compared to TNF-alpha alone. It appeared that TNF-alpha sensitized the cells to irradiation because, when cells were irradiated 24 h after exposure to TNF-alpha, increased cell death was observed. In contrast, irradiation delivered 24 h prior to TNF-alpha exposure did not result in more cell death than after TNF-alpha alone. TNF-alpha induced expression of its own mRNA, but TNF-alpha mRNA induction was neither induced nor enhanced by irradiation. Activation of the transcription factor nuclear factor kappaB can be induced by TNF-alpha and has a modulating antiapoptotic effect. But enhancement of TNF-alpha-induced cell death by irradiation did not result from altered activation of nuclear factor kappaB. TNF-alpha treatment of LNCaP cells resulted in partial activation of caspase-8 and -6 but not caspase-3. There was only minimal poly(ADP-ribose) polymerase cleavage seen in LNCaP cells after exposure to both TNF-alpha and irradiation at 72 h, a time when 60% of the cells were apoptotic. Experiments with peptide inhibitors of cysteine and serine proteases suggested that caspases were the predominant mediators of apoptosis induced by TNF-alpha alone but that serine proteases contributed significantly to cell death induced by TNF-alpha plus irradiation. TNF-alpha increased production of ceramide in LNCaP cells 48 h after exposure. Although irradiation alone had no effect on ceramide production in LNCaP cells, TNF-alpha plus irradiation induced significantly more ceramide than TNF-alpha alone. Ceramide production did not occur immediately after exposure to TNF-alpha, but rather was delayed such that ceramide levels were increased only 24 h after exposure to apoptotic stimuli. Moreover, non-toxic levels of exogenous C2-ceramide sensitized LNCaP cells to irradiation similarly to TNF-alpha, suggesting that one mechanism by which LNCaP cells were sensitized to irradiation was by increased intracellular ceramide. Hence, ceramide generation is a critical component in radiation-induced apoptosis in human prostate cancer cells. Inhibition of ceramide generation may provide a selective advantage in the development of radioresistance in prostate cancer.
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PMID:Tumor necrosis factor-alpha sensitizes prostate cancer cells to gamma-irradiation-induced apoptosis. 1019 36

Activation of either tumor necrosis factor receptor 1 or Fas induces a low level of programmed cell death in LNCaP human prostate cancer cells. We have shown that LNCaP cells are entirely resistant to gamma-radiation-induced apoptosis, but can be sensitized to irradiation by TNF-alpha. Fas activation also sensitized LNCaP cells to irradiation, causing nearly 40% cell death 72 h after irradiation. Caspase-8 was cleaved and activated after exposure to tumor necrosis factor (TNF)-alpha. However, after exposure to anti-Fas antibody caspase-8 cleavage occurred only between the 26-kDa N-terminal prodomain and the 28-kDa C-terminal region that contains the protease components. Although anti-Fas antibody plus irradiation induced apoptosis that could be blocked by the pancaspase inhibitor zVAD, there was no measurable caspase-8 activity after exposure to anti-Fas antibody. The effector caspases-6 and -7, and to a lesser extent caspase-3, were activated by TNF-alpha, but not by anti-Fas antibody. Anti-Fas antibody, like TNF-alpha also activated serine proteases that contributed to cell death. Exposure of LNCaP cells simultaneously to TNF-alpha and anti-Fas antibody CH-11 resulted in marked enhancement of apoptosis that occurred very rapidly and was still further augmented by irradiation. Rapid apoptosis that ensued from combined treatment with TNF-alpha, anti-Fas antibody, and irradiation was completely blocked either by zVAD or expression of dominant negative Fas-associated death domain. Our data shows that there are qualitative differences in caspase activation resulting from either TNF receptor 1 or Fas. Simultaneous activation of these receptors was synergistic and caused rapid epithelial cell apoptosis mediated by the caspase cascade.
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PMID:Tumor necrosis factor-alpha and Fas activate complementary Fas-associated death domain-dependent pathways that enhance apoptosis induced by gamma-irradiation. 1072

We have demonstrated that Apo-2 ligand (Apo-2L)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis of human prostate cancer PC-3, DU145, and LNCaP cells in a dose-dependent manner, with PC-3 cells displaying the greatest sensitivity to Apo-2L/TRAIL. Susceptibility of the prostate cancer cell types to Apo-2L/TRAIL-induced apoptosis did not appear to correlate with the levels of the Apo-2L/TRAIL receptors death receptor (DR) 4 (TRAIL receptor 1) or DR5 (TRAIL receptor 2), decoy receptor (DcR) 1 and DcR2, Flame-1, or the inhibitors of apoptosis proteins family of proteins. Apo-2L/TRAIL-induced apoptosis of PC-3 cells was associated with the processing of caspase-8, caspase-10, and the proapoptotic Bid protein, resulting in the cytosolic accumulation of cytochrome c as well as the processing of procaspase-9 and procaspase-3. Cotreatment with the caspase-8 inhibitor z-IETD-fmk or DR4:Fc significantly inhibited Apo-2L/TRAIL-induced apoptosis. Treatment with paclitaxel or taxotere increased DR4 and/or DR5 protein levels (up to 8-fold) without affecting the protein levels of DcR1 and DcR2, Apo-2L/TRAIL, Fas, or Fas ligand. Up-regulation of DR4 and DR5 was not preceded by the induction of their mRNA levels but was inhibited by cotreatment with cycloheximide. Importantly, sequential treatment of PC-3, DU145, and LNCaP cells with paclitaxel followed by Apo-2L/TRAIL induced significantly more apoptosis than Apo-2L/TRAIL treatment alone (P < 0.01). This was also associated with greater processing of procaspase-8 and Bid, as well as greater cytosolic accumulation of cytochrome c and the processing of caspase-3. These findings indicate that up-regulation of DR4 and DR5 protein levels by treatment with paclitaxel enhances subsequent Apo-2L/TRAIL-induced apoptosis of human prostate cancer cells.
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PMID:Pretreatment with paclitaxel enhances apo-2 ligand/tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of prostate cancer cells by inducing death receptors 4 and 5 protein levels. 1121 79

beta-Lapachone, a novel anti-neoplastic drug, induces various cancer cells to undergo apoptosis. In a previous report, we showed that beta-lapachone-induced apoptosis of HL-60 cells is mediated by oxidative stress. However, in the present study, we found that beta-lapachone-induced apoptosis of human prostate cancer (HPC) cells may be independent of oxidative stress. In contrast to the 10-fold beta-lapachone-induced increase in H(2)O(2) production seen in HL-60 cells, only a 2- to 4-fold increase was observed in HPC cells. N-acetyl-L-cysteine (NAC), a thiol antioxidant, inhibited the apoptosis in DU145 cells after 12 h exposure to beta-lapachone. Nonetheless, NAC, along with other antioxidants, failed to exert similar effect in HPC cells subjected to beta-lapachone treatment for 24 h. Under this premise, we suggest that the oxidative stress may not play a crucial role in beta-lapachone-mediated HPC cell apoptosis. Here we demonstrate that damage to genomic DNA is the trigger for the apoptosis of HPC cells induced by beta-lapachone. According to our results, beta-lapachone stimulates DNA dependent kinase expression and poly(ADP-ribose) polymerase cleavage in advance of significant morphological changes. beta-Lapachone promotes the expression of cyclin-dependent kinase (cdk) inhibitors (p21(WAF1) and p27(Kip1)), induces bak expression, and subsequently stimulates the activation of caspase-7 but not of caspase-3 or caspase-8 during the apoptosis of HPC cells. Taken together, these results suggest that the signaling pathway involving the beta-lapachone-induced apoptosis of HPC cell may be by DNA damage, induction of cdk inhibitors (p21 and p27), and then subsequent stimulation of caspase-7 activation.
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PMID:Induction of CDK inhibitors (p21(WAF1) and p27(Kip1)) and Bak in the beta-lapachone-induced apoptosis of human prostate cancer cells. 1125 23

We find that the prostate cancer cell lines ALVA-31, PC-3, and DU 145 are highly sensitive to apoptosis induced by TRAIL (tumor-necrosis factor-related apoptosis-inducing ligand), while the cell lines TSU-Pr1 and JCA-1 are moderately sensitive, and the LNCaP cell line is resistant. LNCaP cells lack active lipid phosphatase PTEN, a negative regulator of the phosphatidylinositol (PI) 3-kinase/Akt pathway, and demonstrate a high constitutive Akt activity. Inhibition of PI 3-kinase using wortmannin and LY-294002 suppressed constitutive Akt activity and sensitized LNCaP cells to TRAIL. Treatment of LNCaP cells with TRAIL alone induced cleavage of the caspase 8 and XIAP proteins. However, processing of BID, mitochondrial release of cytochrome c, activation of caspases 7 and 9, and apoptosis did not occur unless TRAIL was combined with either wortmannin, LY-294002, or cycloheximide. Blocking cytochrome c release by Bcl-2 overexpression rendered LNCaP cells resistant to TRAIL plus wortmannin treatment but did not affect caspase 8 or BID processing. This indicates that in these cells mitochondria are required for the propagation rather than the initiation of the apoptotic cascade. Infection of LNCaP cells with an adenovirus expressing a constitutively active Akt reversed the ability of wortmannin to potentiate TRAIL-induced BID cleavage. Thus, the PI 3-kinase-dependent blockage of TRAIL-induced apoptosis in LNCaP cells appears to be mediated by Akt through the inhibition of BID cleavage.
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PMID:Elevated AKT activity protects the prostate cancer cell line LNCaP from TRAIL-induced apoptosis. 1127 84

Tachyplesin is an antimicrobial peptide present in leukocytes of the horseshoe crab (Tachypleus tridentatus). In this study, a synthetic tachyplesin conjugated to the integrin homing domain RGD was tested for antitumor activity. The in vitro results showed that RGD-tachyplesin inhibited the proliferation of both cultured tumor and endothelial cells and reduced the colony formation of TSU prostate cancer cells. Staining with fluorescent probes of FITC-annexin V, JC-1, YO-PRO-1, and FITC-dextran indicated that RGD-tachyplesin could induce apoptosis in both tumor and endothelial cells. Western blotting showed that treatment of cells with RGD-tachyplesin could activate caspase 9, caspase 8, and caspase 3 and increase the expression of the Fas ligand, Fas-associated death domain, caspase 7, and caspase 6, suggesting that apoptotic molecules related to both mitochondrial and Fas-dependent pathways are involved in the induction of apoptosis. The in vivo studies indicated that the RGD-tachyplesin could inhibit the growth of tumors on the chorioallantoic membranes of chicken embryos and in syngenic mice.
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PMID:RGD-Tachyplesin inhibits tumor growth. 1128 11

Survival of cancer cells in response to therapy, immune response, or metastasis depends on interactions between pro- and antiapoptotic signals. Two major proapoptotic pathways have been described: (a) a death receptor pathway; and (b) a mitochondrial pathway. We reported previously that Akt and the epidermal growth factor (EGF) receptor send separate, redundant survival signals that act to inhibit the mitochondrial proapoptotic pathway in prostate cancer LNCaP cells. However, it was unclear at what level the pro- and antiapoptotic signals interact in these cells, and it was also unclear whether these signals would inhibit the death receptor pathway. We found that EGF can protect LNCaP cells from apoptosis induced by LY294002 but not from tumor necrosis factor a (TNF-alpha)-induced apoptosis. Furthermore, TNF-alpha induced apoptosis under conditions in which Akt was active. Treatment with TNF-alpha resulted in activation of caspase 8 and cleavage of BID, which in turn induced cytochrome c release and caspase 9-dependent activation of effector caspases. Thus, proapoptotic signals induced by both TNF-alpha and LY294002 converge on mitochondria and trigger cytochrome c release. Because EGF can inhibit cytochrome c release induced by LY294002 but not cytochrome c release induced by TNF-alpha, we suggest that the EGF survival mechanism operates on the mitochondrial pathway at a site upstream of cytochrome c release. The ability of TNF-alpha to bypass survival signals from activated EGF receptor and Akt in prostate cancer cells makes death receptor signaling a promising avenue for therapeutic intervention.
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PMID:Tumor necrosis factor alpha induces BID cleavage and bypasses antiapoptotic signals in prostate cancer LNCaP cells. 1128 52

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

The adaptor protein FADD directly, or indirectly via another adaptor called TRADD, recruits caspase 8 to death receptors of the tumor necrosis factor receptor family. Consequentially, a dominant-negative mutant (FADD-DN, which consists only of the FADD death domain) that binds to receptors but cannot recruit caspase 8 has been widely used to inhibit apoptosis by various stimuli that work via death receptors. Here, we show that FADD-DN also has another cell type- and cancer-dependent activity because it induces apoptosis of normal human prostate epithelial cells but not normal prostate stromal cells or prostate cancer cells. This activity is independent of FADD-DN's ability to bind to three known interacting proteins, Fas, TRADD or RIP suggesting that it is distinct from FADD's functions at activated death receptors. FADD-DN induces caspase activation in normal epithelial cells as demonstrated using a Fluorescence Resonance Energy Transfer assay that measures caspase activity in individual living cells. However, caspase-independent pathways are also implicated in FADD-DN-induced apoptosis because caspase inhibitors were inefficient at preventing prostate cell death. Therefore, the death domain of FADD has a previously unrecognized role in cell survival that is epithelial-specific and defective in cancer cells. This FADD-dependent signaling pathway may be important in prostate carcinogenesis.
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PMID:An apoptosis signaling pathway induced by the death domain of FADD selectively kills normal but not cancerous prostate epithelial cells. 1146 14

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


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