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)

Development of effective therapeutic modalities for the treatment of human cancer relies heavily upon understanding the molecular alterations that result in initiation and progression of the tumorigenic process. Many of the molecular changes identified in human prostate tumorigenesis so far play key roles in apoptosis regulation. Apoptosis represents a universal and exquisitely efficient cellular suicide pathway. Since the therapeutic goal is to trigger tumor-selective apoptotic cell death (without clinically significant effects on the host), elucidation of the mechanisms underlying apoptosis deregulation will lead to the identification of specific cellular components for targeting therapeutic interventions. As our understanding of its vital role in the development and growth of the prostate gland has expanded, numerous genes that encode apoptotic regulators have been identified that are severely impaired in prostate cancer cells. In addition, the expression of apoptotic modulators within prostatic tumors appears to correlate with tumor sensitivity to traditional therapies such as hormonal ablation and radiotherapy. No strict correlation between apoptosis induction and a patient's long-term prognosis has emerged, perhaps due to the fact that the ability to achieve initial remission alone does not adequately predict long-term outcome. This review will encompass the known molecular changes intimately involved in the apoptotic pathway which have potential prognostic value in disease progression, as well as therapeutic significance in the enhancement of the apoptotic response to novel and established treatment strategies for the treatment of androgen-dependent and androgen-independent prostatic tumors. The main focus will be on the role of the transforming growth factor-beta (TGF-beta) signaling pathway, bcl-2 and the bcl-2 family members, the caspase cascade (apoptosis executioners), and the Fas pathway in induction and regulation of apoptosis following therapeutic stimuli for the management of advanced prostate cancer.
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PMID:Apoptosis in prostate carcinogenesis. A growth regulator and a therapeutic target. 1092 88

Several laboratories have attempted with little success to induce Fas-mediated apoptosis in prostate cancer (PCa) cells, using different external Fas agonists, i.e., anti-Fas antibodies and membrane-bound FasL. The present study confirms these earlier results using the anti-Fas antibody CH-11 in five human PCa cell lines (PPC-1, LNCaP, PC-3, TSU-Pr1, and DU145). However, intracellular murine FasL expression induced Fas-mediated apoptosis in all CH-11-resistant cell lines. Adenovirus (AdGFPFasL(TET)) was used to deliver a Murine FasL-GFP fusion gene into human PCa cells resulting in 70-98% apoptosis at 48 h as determined by the MTS assay. DU145 and PPC-1 cells treated with AdGFPFasL(TET) stained positive for the TUNEL assay, indicating that cell death was via apoptosis. Using immunofluorescent microscopy, Fas and GFPFasL colocalized to the same intracellular compartment. The anti-Fas neutralizing antibody ZB-4 was unable to block AdGFPFasL(TET)-mediated cell death, suggesting that intracellular FasL may ligate Fas within the Golgi and/or endoplasmic reticulum. This is the first evidence suggesting that these two molecules interact prior to cell surface presentation. Collectively, these findings indicate that intracellular GFPFasL expression is superior to CH-11 at inducing Fas-mediated apoptosis in human PCa cells and may allow use of AdGFPFasL(TET) for PCa gene therapy.
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PMID:Intracellular Fas ligand expression causes Fas-mediated apoptosis in human prostate cancer cells resistant to monoclonal antibody-induced apoptosis. 1102 Mar 50

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

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

In patients with localized prostate cancer, radical prostatectomy and radiation therapy, although effective in controlling localized disease, are often associated with significant side effects attributable to injury of adjacent tissues. Moreover, patients with metastatic disease eventually fail systemic hormonal or chemotherapy because of the development of progressive, refractory disease. In this study, we evaluated the safety and efficacy of a novel suicide gene therapy that could potentially spare normal tissue while bypassing molecular mechanisms of apoptosis resistance by using chemically inducible effector caspases to trigger apoptosis in prostate cancer cells. Initially, we compared the ability of a panel of inducible Fas signaling intermediates to kill human and murine prostate cancer cell lines. On the basis of the superior killing by downstream caspase-1 and caspase-3, replication-deficient adenoviral vectors expressing conditional caspase-1 (Ad-G/iCasp1) or caspase-3 (Ad-G/iCasp3), regulated by nontoxic, lipid-permeable, chemical inducers of dimerization (CID), were constructed. Upon vector transduction followed by CID administration, aggregation and activation of these recombinant caspases occur, leading to rapid apoptosis. In vitro, both human (LNCaP and PC-3) and murine (TRAMP-C2 and TRAMP-C2G) prostate cancer cell lines were efficiently transduced and killed in a CID-dependent fashion. In vivo, direct injection of Ad-G/iCasp1 into s.c. TRAMP-C2 tumors caused focal but extensive apoptosis without evidence for a bystander effect at the maximal viral dose (i.e., 2.5 x 10(10) viral particles/25 microl) in host animals that also received CID compared with control animals. Treatment with Ad-G/iCasp1 plus CID resulted in a transient, yet significant, reduction both in tumor growth and volume compared with tumors treated with vector but not CID (P < 0.035) or vector-diluent plus CID (P < 0.022), both of which grew more rapidly. These results demonstrate that CID-regulated, caspase-based suicide gene therapy is safe and can inhibit the growth of experimental prostate cancer in vitro and in vivo through potent induction of apoptosis, providing a rationale for further development.
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PMID:Adenovirus-mediated transfer of inducible caspases: a novel "death switch" gene therapeutic approach to prostate cancer. 1128 32

Fas (Apo-1/CD95) is a cell-surface receptor involved in cell death signaling through binding of Fas ligand. Mutations of the Fas gene might be involved in proliferative diseases of the prostate by prolongation of programmed cell death of prostatic epithelial cells. Using the laser capture microdissection method, Fas gene mutations were examined on genomic DNA extracted from lesions with high-grade prostatic intraepithelial neoplasia (HGPIN), a possible precursor of prostatic cancer (PCA), and from PCA. A total of 193 lesions, 111 with HGPIN, 55 with PCA, and 27 benign glands, were microdissected from 27 patients with PCA. Polymerase chain reaction-amplified products were directly sequenced. Loss of heterozygosity (LOH) was examined at four sites of known polymorphisms. Fas gene mutations were detected in HGPIN: 4 of 27 (14.8%) cases or 4 of 111 (3.6%) lesions. All were point mutations: three missense and one nonsense in the death domain. Benign proliferative glands adjoining HGPIN and/or PCA, and PCA never showed mutations. LOH was found in 31.3% of PCA and 25% of HGPIN lesions, but was never found in benign glands. Exclusive occurrence of Fas mutations in HGPIN might underlie the development of these lesions. Occasional findings of LOH in HGPIN and PCA suggested that genetic instability might occur during the early phase of prostatic carcinogenesis.
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PMID:Fas gene mutations in prostatic intraepithelial neoplasia and concurrent carcinoma: analysis of laser capture microdissected specimens. 1131 Aug 21

Androgen plays a critical role in the promotion and growth of prostate cancer. Androgen ablation has an expanding role in prostate cancer treatment and is now used to improve the efficacy of radiation therapy in addition to its role in treatment of metastatic disease. Here we show that androgen interferes with induction of prostate cancer cell death induced by a variety of stimuli. The effect of androgen on cell death occurs predominantly by interference with caspase activation and the inhibition of caspase cleavage in both the extrinsic and intrinsic cell death pathways. Androgen inhibited apoptosis induced by both tumor necrosis factor alpha (TNF-alpha) and by Fas activation with or without concomitant irradiation. An antiapoptotic effect was seen in the presence of R1881, dihydrotestosterone, and also 17beta-estradiol within 24 h of death induction. Sustained inhibition of apoptosis at 72 h was seen only with R1881, dihydrotestosterone, cyproterone acetate, and hydroxyflutamide. Androgen treatment inhibited activation of caspases-8, -7, and -9 by TNF-alpha +/- irradiation. Androgen attenuated BAX expression and blocked appearance of the proapoptotic p18 fragment of BAX. Androgen also abrogated BID cleavage induced by TNF-alpha + irradiation that contributed to a decrease in cytochrome c egress from mitochondria induced by TNF-alpha +/- irradiation. There was also decreased mitochondrial depolarization in response to TNF-alpha + irradiation. Production of the proapoptotic lipid metabolite ceramide was not affected by androgen, but androgen acted downstream from ceramide generation because R1881 blocked cell-death induction by bacterial sphingomyelinase. Inhibition of phosphoinositol-3-kinase activity by wortmannin induced apoptosis that was also blocked by androgen, but there was no effect on protein levels or phosphorylation of AKT, indicating that R1881 did not interact with survival signaling of phosphoinositol-3-kinase. Lastly, androgen inhibited activation of nuclear factor-kappaB during death induction, but the effect of androgen on cell death was not mediated by interference with the nuclear factor-kappaB pathway. The data suggest that androgen induced blockade of caspase activation in both intrinsic and extrinsic cell death pathways and thereby was able to protect prostate cancer cells from apoptosis induced by diverse stimuli.
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PMID:Androgen blocks apoptosis of hormone-dependent prostate cancer cells. 1145 15

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

Ligation of the Fas receptor (FasR) is a key step in apoptosis induction. Using a series of human tumor cells (SNB19, SNB79, 143N2, and SHEP), we observed a distinct efficacy of human anti-FasR antibody with an apparent correlation with Fas cell surface antigen expression. In contrast, all cells studied expressed detectable FasR mRNA transcripts. For all anti-FasR antibody-sensitive tumor cells, we showed a similar efficacy of Mab according to dose fractionation and injection site. We showed that, when injected into nude mice bearing human osteosarcoma 143N2, neuroblastoma SHEP, prostatic cancer PAC120, and the two glioblastomas SNB19 and SNB79, anti-FasR Mab induces significant inhibition of the growth rate of 143N2, SHEP, and PAC120 tumors, but has no efficacy on SNB19 and SNB79 tumors, with a relationship between in vitro and in vivo sensitivity to anti-FasR antibody. Altogether, these results suggest the antitumor potential of anti-FasR antibody in human neoplasms.
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PMID:Distinct experimental efficacy of anti-Fas/APO-1/CD95 receptor antibody in human tumors. 1147 42

In a mouse model of prostate cancer, adenovirus-mediated interleukin-12 (Ad.mIL-12) gene therapy resulted in significant growth inhibition of both the injected primary tumor and synchronous metastases. Within 2 days of vector injection, two distinct patterns of apoptosis were detected within the primary tumor, the inhibition of which with a caspase inhibitor substantially negated growth suppression. The dominant pattern displayed localized sheets of apoptotic cells in close association with necrosis containing polymorphic neutrophils (PMNs). Depletion of PMNs resulted in the loss of this pattern of apoptosis and reduced growth suppression. A second major wave of growth suppression within the primary tumor was mediated by an immune response. Natural killer (NK) cell activity was detected within tumor-infiltrating lymphocytes (TIL) by the eighth day post-vector injection, the depletion of which resulted in a significant loss of survival enhancement. A more modest role for T cells was identified, which in the absence of documented cytotoxic T lymphocyte (CTL) activity may be related to a significant reduction in interferon-gamma (IFN-gamma) levels found in mice depleted of T cells, thereby reducing the secondary influences of IFN-gamma. However, depletion of NK cells or T cells had no discernible negative effect on IL-12-mediated anti-metastatic activity. Attention focused on the role of IFN-gamma, observed following Ad.mIL-12 therapy, to mediate the diffuse pattern of apoptosis seen in the primary and metastatic lesions. In vitro studies noted the ability of IFN-gamma to up-regulate tumor cell expression of Fas and FasL to mediate apoptosis, whereas in vivo blockage of Fas/FasL interactions with soluble Fas resulted in a modest reduction in primary tumor growth suppression but complete abrogation within metastatic lesions.
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PMID:Independent contributions of GR-1+ leukocytes and Fas/FasL interactions to induce apoptosis following interleukin-12 gene therapy in a metastatic model of prostate cancer. 1150 92


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