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)

bcl-xL is an antiapoptotic protein that shares sequence homology with bcl-2 and seems to convey chemoresistance in many human tumor cell lines. bcl-xL protein is expressed at a 3-fold higher level in PC-3 cells than it is in LNCaP cells. Taxol causes apoptosis in both these cell lines, as measured by the formation of DNA ladders and by the observation of typical cellular morphological changes (chromatin condensation and nuclear fragmentation) after 4', 6-diamidino-2-phenylindole staining. Overexpression of bcl-2 in LNCaP cells did not prevent Taxol-induced apoptosis. Treatment of LNCaP cells with 10 nm Taxol led, after 24 h, to relatively specific and almost total down-regulation of bcl-xL protein in the absence of alteration of bax, bak, or bcl-2 levels. This change was paralleled by a similar decrease in the level of bcl-xL mRNA, as demonstrated by reverse transcription-PCR. The level of glyceraldehyde-3-phosphate dehydrogenase mRNA was not changed. In PC-3 cells, 48 h were required for both maximal bcl-xL protein down-regulation and cellular apoptosis. In contrast, treatment of LNCaP cells with estramustine induced apoptosis, but this was not associated with any change in the intracellular level of bcl-xL or bax protein. Instead, relatively specific 2-fold up-regulation of the proapoptotic protein bak was observed. In PC-3 cells, cellular apoptosis induced by estramustine was bak independent. These results augment our understanding of the importance of bcl-xL in prostate cancer and suggest that appropriate manipulation of cytotoxic chemotherapeutic agents may favorably alter the balance between pro- and antiapoptotic proteins in this tumor.
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PMID:Taxol and estramustine-induced modulation of human prostate cancer cell apoptosis via alteration in bcl-xL and bak expression. 981 95

The frequency of bcl-2 protein expression was evaluated using immunocytochemical staining during the progression of human and rat prostate cancer from an androgen-sensitive nonmetastatic to an androgen-independent metastatic phenotype. Previous studies (A. S. Shabaik et al., J. Urol. Pathol., 3: 17-27, 1995) demonstrated that 0 of 20 high-grade prostatic intraepithelial neoplasias and only 3 (7%) of 41 pathologically localized stage B human prostatic cancers had detectable bcl-2 staining. In the present study, 5 (17%) of 30 lymph node metastases from pathologically disseminated D1 disease and 14 (52%) of 27 bone metastases from pathologically disseminated D2 disease expressed detectable bcl-2 protein. These data demonstrate that there is a statistically significant (P < 0.05) association between expression of bcl-2 and the progression of human prostatic cancer cells to a metastatic phenotype. Such bcl-2 expression is not absolutely required, however, for either androgen independence or metastatic ability by human prostatic cancer cells. Likewise, within a series of eight distinct Dunning R3327 rat prostatic cancer sublines, which differ widely in their progressional state, there is also a significant association (P < 0. 05) between bcl-2 expression and progression (four of six androgen-independent rat sublines expressed bcl-2 protein). Again in this rodent system, bcl-2 expression is not an absolute requirement for either androgen independence or metastatic ability. For example, the androgen-independent highly metastatic Dunning AT-3 subline, while expressing bax protein, does not express bcl-2 protein. If such AT-3 cells are genetically engineered to express bcl-2, these expressing cells are now cross-resistant to a variety of mechanistically diverse noxious insults (e.g., viral infection or exposure to antimetabolites, alkylating agents, or agents which elevate the intracellular free Ca2+). The ability of bcl-2 to inhibit the programmed death of AT-3 cells induced by these agents involves a late step in the death process, since the early induction of expression of a series of genes associated with apoptosis is not impaired by bcl-2 expression. These data demonstrate that the development of androgen independence and/or metastatic ability can be associated with the expression of bcl-2 protein but that bcl-2-independent mechanisms also exist for such progression.
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PMID:Expression of bcl-2 and the progression of human and rodent prostatic cancers. 981 82

Previously we reported that proteasome inhibitors were able to overcome Bcl-2-mediated protection from apoptosis. Here we show that inhibition of the proteasome activity in Bcl-2-overexpressing cells accumulates the proapoptotic Bax protein to mitochondria/cytoplasm, where it interacts to Bcl-2 protein. This event was followed by release of mitochondrial cytochrome c into the cytosol and activation of caspase-mediated apoptosis. In contrast, proteasome inhibition did not induce any apparent changes in Bcl-2 protein levels. In addition, treatment with a proteasome inhibitor increased levels of ubiquitinated forms of Bax protein, without any effects on Bax mRNA expression. We also established a cell-free Bax degradation assay in which an in vitro-translated, (35)S-labeled Bax protein can be degraded by a tumor cell protein extract, inhibitable by addition of a proteasome inhibitor or depletion of the proteasome or ATP. The Bax degradation activity can be reconstituted in the proteasome-depleted supernatant by addition of a purified 20S proteasome or proteasome-enriched fraction. Finally, by using tissue samples of human prostate adenocarcinoma, we demonstrated that increased levels of Bax degradation correlated well with decreased levels of Bax protein and increased Gleason scores of prostate cancer. Our studies strongly suggest that ubiquitin/proteasome-mediated Bax degradation is a novel survival mechanism in human cancer cells and that selective targeting of this pathway should provide a unique approach for treatment of human cancers, especially those overexpressing Bcl-2.
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PMID:Bax degradation by the ubiquitin/proteasome-dependent pathway: involvement in tumor survival and progression. 1072

In prostate carcinoma, overexpression of the anti-apoptotic gene Bcl-2 has been found to be associated with resistance to therapies including radiation and androgen ablation. Restoring the balance of Bcl-2 family members may result in the induction of apoptosis in prostate cancer cells previously resistant to treatment. To accomplish this, a strategy involving overexpression of the pro-apoptotic gene Bax was executed. The use of cytotoxic genes such as Bax require selective expression of the gene. In this study, we examined the ability of selective expression of Bax protein directed by a prostate-specific promoter to induce apoptosis in human prostate carcinoma. A second-generation adenoviral vector was constructed with the modified prostate-specific probasin promoter, ARR2PB, directing expression of an HA-tagged Bax gene and a green fluorescent protein reporter translated from an internal ribosome entry site (ARR2PB.Bax.GFP). ARR2PB promoter activity is tightly regulated and highly prostate specific and is responsive to androgens and glucocorticoids. The prostate-specific promoter-Bax-GFP transgene cassette was inserted into a cloning site near the right inverted terminal repeat of the adenoviral vector to retain specificity of the promoter. LNCaP cells infected with Ad/ARR(2)PB.Bax.GFP showed high levels of Bax expression 48 h after infection resulting in an 85% reduction in cell viability. Importantly, LNCaP cells stably transfected to overexpress Bcl-2 showed similar patterns of cell death when infected with Ad/ARR(2)PB.Bax.GFP, an 82% reduction in cell viability seen 48 h after infection. Apoptosis was confirmed by measuring caspase activation and using the TUNEL assay. Tissue specificity was evaluated using A549 cells (lung adenocarcinoma), SK-Hep-1 (liver cancer) cells, and Hela (cervical cancer) cells which did not show detectable expression of virally delivered Bax protein or any increase in cell death. Systemic administration of Ad/ARR2PB. Bax.GFP in nude mice revealed no toxicity in liver, lung, kidney, or spleen. This study shows that infection with the second-generation adenovirus, ARR2PB.Bax.GFP, results in highly specific cytotoxicity in LNCaP cells, and that consequent overexpression of Bax in prostate carcinoma, even in the context of high levels of Bcl-2 protein, resulted in apoptosis. These results suggest that a second-generation adenovirus-mediated, prostate-specific Bax gene therapy is a promising approach for the treatment of prostate cancer.
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PMID:Prostate-specific expression of Bax delivered by an adenoviral vector induces apoptosis in LNCaP prostate cancer cells. 1157 75

Nonmelanoma skin cancer (NMSC) is the most frequently diagnosed form of cancer in United States. We have previously described the tumor suppressor role of bax protein in skin carcinogenesis as well as the ability of bax to modulate the apoptotic response of keratinocytes following ultraviolet irradiation. Moreover, we have demonstrated an increase in tumor incidence in bax-null mice compared to control littermates in an in vivo chemical carcinogenesis experiment. In this study, we examined the contribution of bax protein in repair of UVR-mediated DNA lesions. The level of cyclobutane pyrimidine dimers remaining was twofold greater in UVR-treated primary keratinocytes from bax-deficient mice than that of control cells at 48 h (P < 0.03). Similar results were obtained using embryonic fibroblasts and also with a bax-deficient prostate cancer cell line. However, the repair rate of 6-4 pyrimidine pyrimidone photoproducts was unaffected by the absence of bax protein. These findings suggest that bax may have a dual function in its role as tumor suppressor in NMSC. Bax may directly or indirectly facilitate either DNA repair or cell death. Either function would be anticipated to enhance genomic integrity following a genotoxic event through repair or deletion of the damaged cell.
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PMID:Evidence that nucleotide excision repair is attenuated in bax-deficient mammalian cells following ultraviolet irradiation. 1216 71

Ionizing radiation caused induction NF kappa B activity and Bcl-2 protein expression in the radioresistant p53 null human prostate cancer cell line, PC-3. Exposure of PC-3 cells to Ad5-I kappa B super-repressor inhibited radiation-induced Bcl-2 expression indicating that radiation-induced NF kappa B activity is required for the induction of Bcl-2 protein. PAR-4, a novel pro-apoptotic protein is a potent down-modulator of NF kappa B activity and bcl-2 protein expression. This study was undertaken to investigate the impact of PAR-4 expression on radiation-induced NF kappa B activity and Bcl-2 expression and its resultant radiation response in PC-3 cells. Western blot analysis indicated that enforced expression of PAR-4 in PC-3 cells down regulated radiation-induced bcl-2 protein, whereas in vector transfected cells radiation caused an induction of bcl-2 protein. In both transfectant cell lines, the bax protein levels remained unaltered after radiation. When compared to PC-3/Vector cells, PC-3/PAR-4 cells showed significant sensitivity to radiation-induced clonogenic inhibition and apoptosis. Thus, the down-regulation of bcl-2 protein by ectopic PAR-4 expression altered bcl-2: bax ratio in PC-3/PAR-4 cells and this led enhanced radiosensitivity. PAR-4 was found to inhibit the radiation-induced NF kappa B activity and NF kappa B transcriptional activity is essential for bcl-2 upregulation. In PC-3/Vector cells, radiation caused an increase in NF kappa B activity leading to upregulation of bcl-2 protein. However, in PC-3/PAR-4 cells, the radiation-induced NF kappa B activity was inhibited resulting in the transrepression of bcl-2 promoter and down-modulation of bcl-2 protein. In addition, PAR-4 was found to directly inhibit the phosphorylation and degradation of I kappa B alpha, which led to the loss of NF kappa B activity causing repression of endogenous and radiation-induced Bcl-2 protein. Together, these mechanisms suggest that PAR-4 is functionally required to cause radiation-induced apoptosis by abrogating the survival and anti-apoptotic effects of NF kappa B activity and bcl-2 function respectively.
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PMID:Par-4, a pro-apoptotic gene, inhibits radiation-induced NF kappa B activity and Bcl-2 expression leading to induction of radiosensitivity in human prostate cancer cells PC-3. 1221 14

Using a binary co-transfection strategy of Ad/GT Bax and Ad/PGK-GV16, we have succeeded in inducing overexpression of Bax protein in three prostate cell lines (androgen-insensitive DU145 and PC3, and androgen-sensitive LNCaP). The expression of Bax protein by this system was sufficient to induce all three prostate lines to undergo apoptosis. The fact that DU145 cells which have a p53 mutation and are deficient in Bax, responded to this treatment, suggests that this effect is independent of these pathways. Initiation of the cleavage of Caspase-3 (CPP32/Yama/apopain) and PARP (poly (ADP-ribose) polymerase) by the introduction of Bax were confirmed by western blot analysis. Bcl-2 expression is relevant in the progression of prostate cancer and contributes to an androgen, apoptotic-resistant phenotype in the advanced stages. We examined stable Bcl-2 overexpressing DU145, PC3 and LNCaP cell lines as models of advanced prostate cancer. The adenoviral co-transfection system induced Bax protein expression and apoptosis even in these Bcl-2 transfected cell lines. Taken together, our results suggest that this Bax expression system might represent a useful gene therapy strategy when applied to the treatment of prostate cancer and its efficacy would be independent of the Bcl-2 status and androgen sensitivity of these cancers.
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PMID:A recombinant adenovirus expressing wild-type Bax induces apoptosis in prostate cancer cells independently of their Bcl-2 status and androgen sensitivity. 1217 Jul 76

In this study, we investigated the influence of Bcl-2 overexpression on the radiosensitizing potential of Didox (DX; 3,4-Dihydroxybenzohydroxamic acid), a novel ribonucleotide reductase inhibitor, in p53-null prostate cancer cell line PC-3. The PC-3 cells were transfected with vector alone or ectopically overexpressed with CMV-Bcl-2 construct. The effect of radiation (IR) or DX alone and in combination (pre and post IR exposure of DX) on cell survival was determined by colony-forming assay. The impact of these two treatments on the cell cycle was determined by flow cytometry. To further understand the molecular mechanism of DX-mediated radiosensitization, induction of pro-survival and pro-apoptotic factors were determined by Western blot and gel-shift assays respectively. When compared to PC-3/Bcl-2 cells (SF(2)=0.84; D(0)=437cGy), the PC-3/vector cells (SF(2)=0.4; D(0)=235cGy) were significantly sensitive to ionizing radiation (p<0.001). Exposure of DX at 5 microM concentration prior or post to radiation in both PC-3/vector and PC-3/Bcl-2 transfectants caused an increase in radiation enhancement ratios. A significant reduction in G(2)M phase was observed in cells exposed to DX post IR when compared to cells exposed to IR alone. Exposure to DX after radiation in PC-3/vector significantly abrogated radiation-induced Bcl-2 upregulation, with a concomitant induction of bax protein. In PC-3/Bcl-2 transfectants, DX exposure after IR caused an induction of bax protein. Gel shift assays indicated that in PC-3/vector cells when exposed to IR caused an induction of NFkappa-B activity however, DX down regulated the NFkappa-B activity. Radiation-induced NFkappa-B activity was abrogated in pre and post DX exposure in combination with IR. These findings indicate that DX mediates a potent radiosensitizing effect in p53 null prostate cancer cells by overcoming radiation induced NFkappa-B activity and Bcl-2 expression.
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PMID:Didox (a novel ribonucleotide reductase inhibitor) overcomes Bcl-2 mediated radiation resistance in prostate cancer cell line PC-3. 1249 86

The progression of prostate cancer from androgen-responsive to an androgen-unresponsive state remains the greatest obstacle in the treatment of this disease. Androgen-unresponsive prostate cancer is highly resistant to chemotherapy and radiation treatment that kill cells by the induction of apoptosis. Elucidating the molecular mechanisms of apoptosis regulation in prostate cancer can be useful in the development of new strategies for effective therapy of androgen-unresponsive cancer. We analyzed the Bcl-2 family of apoptosis regulators using various passages of the LNCaP prostate cancer cell line, which serve as an in vitro model for the progression of prostate cancer from androgen-responsive to androgen-unresponsive. In our model, progressively higher passages of LNCaP cells represent the progression to androgen-unresponsiveness. We examined the basal mRNA expression of the Bcl-2 family of apoptosis regulators. Under normal growth conditions, both androgen-responsive and androgen-unresponsive LNCaP cells express the Bcl-2 family of genes at similar levels. Western blot analysis showed the presence of Bcl-2 protein in androgen-responsive cells but not in androgen-unresponsive cells. Both androgen-responsive and androgen-unresponsive cells expressed Bax protein at similar levels. When exposed to oxidative stress, androgen-responsive cells underwent apoptosis but androgen-unresponsive cells exhibited resistance suggesting that the progression to androgen-unresponsiveness was associated with altered regulation of apoptosis. Treatment with paclitaxel or sodium butyrate induced apoptosis in both androgen-responsive and androgen-unresponsive cells suggesting that the apoptotic machinery is still intact in androgen-unresponsive LNCaP cells.
Prostate Cancer Prostatic Dis 2002
PMID:Regulation of Bcl-2 during androgen-unresponsive progression of prostate cancer. 1249 88

Resveratrol, a polyphenolic phytoalexin found in grapes, may have potential for the prevention and treatment of human cancer. We report here that resveratrol inhibits the growth of human prostate carcinoma DU145 cells and provide a molecular explanation of the effect. Resveratrol treatment in DU145 cells resulted in a dose-dependent inhibition of cell growth and induced apoptotic cell death. The antiproliferative effect of resveratrol was associated with the inhibition of D-type cyclins and cyclin-dependent kinase (Cdk) 4 expression, and the induction of tumor suppressor p53 and Cdk inhibitor p21. Moreover, the kinase activities of cyclin E and Cdk2 were inhibited by resveratrol without alteration of their protein levels. Resveratrol treatment also up-regulated the Bax protein and mRNA expression in a dose-dependent manner; however, Bcl-2 and Bcl-xL levels were not significantly affected. These effects were found to correlate with an activation of caspase-3 and caspase-9. Taken together, our study suggests that resveratrol has a strong potential for development as an agent for the prevention of human prostate cancer.
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PMID:Antiproliferative effect of resveratrol in human prostate carcinoma cells. 1497 34


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