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)

Imbalances in the epithelial-stromal interactions are important in the pathogenesis of prostate cancer. However, we know little about androgenic regulation in the stroma of prostate cancer. We examined the cancer-stromal interaction paying attention to androgen responsiveness of stromal side. In co-culture, PC3 and LNCaP cells did not affect dihydrotestosterone (DHT)-dependent growth of prostate stromal cells (PrSCs), but DU145 cells significantly reduced it. Conditioned medium from DU145 cells (DU145-CM) also inhibited DHT-dependent PrSCs growth, androgen receptor (AR) expression, and prostate specific antigen transcription. Although the inhibitory effect of DU145-CM was not affected by neutralizing antibody against EGF, FGF-2, or TNF-alpha, pretreatment with testosterone-Sepharose partially reduced the inhibitory ability of DU145-CM. These results suggest that DU145 cells produce inhibitory factors for androgen responsiveness, including steroid-binding protein(s), and these may participate in crosstalk between DU145 cells and PrSCs as modulators of androgen.
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PMID:Androgen-independent prostate cancer DU145 cells suppress androgen-dependent growth of prostate stromal cells through production of inhibitory factors for androgen responsiveness. 1281 65

Antiandrogens such as Casodex (Bicalutamide) are designed to treat advance stage prostate cancer by interfering with androgen receptor-mediated cell survival and by initiating cell death. Treatment of androgen sensitive, non-metastatic LNCaP human prostate cancer cells with 0-100 microM Casodex or 0-10 ng/ml TNF-alpha induces cell death in 20-60% of the cells by 48 h in a dose-dependent manner. In cells treated with TNF-alpha, this is accompanied by the loss of mitochondrial membrane potential (DeltaPsim) and cell adhesion. In contrast, cells treated with Casodex display loss of cell adhesion, but sustained mitochondrial dehydrogenase activity. Overexpression of Bcl-2 in LNCaP cells attenuates the induction of cell death by TNF-alpha but not Casodex, suggesting that mitochondria depolarization is not required for the induction of cell death by Casodex. While both TNF-alpha and Casodex-induced release of cytochrome c in LNCaP cell is predominantely associated with the translocation and cleavage of Bax, our data also suggest that Casodex induces cell death by acting on components downstream of decline of DeltaPsim and upstream of cytochrome c release. Furthermore, while induction of both caspase-3 and caspase-8 activities are observed in TNF-alpha and Casodex-treated cells, a novel cleavage product of procaspase-8 is seen in Casodex-treated cells. Taken together, these data support the hypothesis that Casodex induces cell death by a pathway that is independent of changes in DeltaPsim and Bcl-2 actions and results in an extended lag phase of cell survival that may promote the induction of an invasive phenotype after treatment.
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PMID:Antiandrogen-induced cell death in LNCaP human prostate cancer cells. 1281 59

The principle of promoter-targeted gene delivery was used to direct the expression of reporter genes and inducible caspases to Cox-2-overexpressing cancer cells. The polycation poly(ethylenimine) was used in unmodified form to nonvirally deliver genes into cells, and targeting was achieved at the transcriptional level. Results demonstrated that reporter expression was reduced by an average of 89.8% in normal cells and cell lines not overexpressing Cox-2 when the strong cytomegalovirus promoter was replaced with the human Cox-2 promoter in delivered plasmids. Cocultures of normal and Cox-2-overexpressing cancer cells showed less than 0.5% reporter expression in normal fibroblast cells but over 35% reporter expression in PC3 prostate cancer cells. This targeting method was then used to direct the expression of inducible forms of caspases 3 and 9 to Cox-2-overexpressing cancer cells of the bladder and prostate. Following activation of the resulting caspase pro-forms, cells underwent apoptosis as evidenced by DNA fragmentation and cytoskeletal degradation. This result was also observed in cells resistant to apoptosis in terms of TNF-alpha initiation. Such directed apoptosis could eventually serve as a treatment for an entire class of Cox-2-overexpressing carcinomas.
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PMID:Directed apoptosis in Cox-2-overexpressing cancer cells through expression-targeted gene delivery. 1290 Jul 68

Cell adhesion molecules (CAMs) play an important role in cancer metastasis by facilitating attachment to vascular endothelia, invasion and spread into secondary tissue sites. We have shown that activated eosinophils (EosA) inhibited the growth of prostate cancer (Pca) cells in vitro. In the present study, we examined the ability of EosA 24 hr conditioned supernatants (EosAcs) to modulate the expression of ICAM-1, VCAM-1, ELAM-1, E-cadherin and N-cadherin expression on human Pca cell lines, Du-145 and PC-3 by flow cytometry. TNF-alpha, IL-10 and IL-12 were also evaluated. ICAM-1, expressed on PC-3 and DU 145 cells, was enhanced by TNF-alpha and IL-10. ELAM-1 was present on DU 145 cells but absent on PC-3. TNF-alpha and IL-10 enhanced ELAM-1 on DU 145, but EosA 24 hr supematants failed to do so. All three cytokines, namely IL-10, IL-12 and TNF-alpha-induced ELAM-1 on PC-3 tumor cells. Although VCAM-1 was absent on DU 145 and PC-3 cells, it was expressed on DU-145 cells after exposure to EosA: tumor cell co-cultures, and was expressed on PC-3 following exposure to IL-10 and IL-12. N-cadherin and E-cadherin were both expressed on DU-145. While N-cadherin was expressed on PC-3 cells, E-cadherin was not. N-cadherin was enhanced on DU-145 and PC-3 cells following exposure to EosA co-culture and upregulated on PC-3 by IL-10 and EosA 24 hr supernatants, but decreased by IL-12. E-cadherin was up-regulated on DU 145 cells following co-culture with EosA and was induced on PC-3 by IL-10 and IL-12, but not by EosA co-culture and 24 hr supematants. In conclusion, inflammatory and non-inflammatory cytokines modulate CAM expression on Pca cells; EosA and EosA 24 hr supernatants also exerted modulatory activity of CAM expression. Most significantly, the metastasis suppressor molecule, E-cadherin was enhanced on DU 145 cells by EosA and induced on PC-3 by IL-10 and IL-12 both of which are produced by EosA. This suggests potential use of these cytokines in immunotherapeutic strategies for prostate cancer and its metastasis.
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PMID:Activated eosinophils upregulate the metastasis suppressor molecule E-cadherin on prostate tumor cells. 1468 82

Neuroendocrine (NE) differentiation is a hallmark of advanced, androgen-independent prostate cancer, for which there is no successful therapy. NE tumor cells are nonproliferating and escape apoptotic cell death; therefore, an understanding of the apoptotic status of the NE phenotype is imperative for the development of new therapies for prostate cancer. Here, we report for the first time on alterations in intracellular Ca(2+) homeostasis, which is a key factor in apoptosis, caused by NE differentiation of androgen-dependent prostate cancer epithelial cells. NE-differentiating regimens, either cAMP elevation or androgen deprivation, resulted in a reduced endoplasmic reticulum Ca(2+)-store content due to both SERCA 2b Ca(2+) ATPase and luminal Ca(2+) binding/storage chaperone calreticulin underexpression, and to a downregulated store-operated Ca(2+) current. NE-differentiated cells showed enhanced resistance to thapsigargin- and TNF-alpha-induced apoptosis, unrelated to antiapoptotic Bcl-2 protein overexpression. Our results suggest that targeting the key players determining Ca(2+) homeostasis in an attempt to enhance the proapoptotic potential of malignant cells may prove to be a useful strategy in the treatment of advanced prostate cancer.
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PMID:Ca2+ homeostasis and apoptotic resistance of neuroendocrine-differentiated prostate cancer cells. 1468 64

In this study we compared the role of TNF-alpha in the regulation of growth and apoptosis in normal human prostate epithelial cells (NP) and prostate tumor cell lines PC3 and LNCap. The NP and PC3 cells were resistant whereas the LNCap cell line was highly sensitive to TNF-alpha induced growth arrest and apoptosis. The resistance of NP and PC3 cells was mediated via an NF-kB survival pathway as treatment of resistant cells with TNF-alpha was accompanied by phosphorylation of I-kBalpha and translocation of NF-kB to the nucleus. TNF-alpha did not induce phosphorylation of I-kB in the sensitive LNCap cells. The sensitivity of LNCap cells involved a cysteine protease cascade as Z-VAD-CH2 F reversed the sensitivity of LNCap cells and induced resistance to TNF-alpha. The differences in susceptibilities to TNF-alpha induced apoptosis of NP and certain prostate tumor cells offer intriguing possibilities for the treatment of prostate cancer without affecting the normal prostate tissue.
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PMID:TNF-alpha-mediated apoptosis in normal human prostate epithelial cells and tumor cell lines. 1473 22

Curcumin (Diferuloylmethane) is a major chemical component of turmeric (curcuma longa) and is used as a spice to give a specific flavor and yellow color in Asian food. Curcumin exhibits growth inhibitory effects in a broad range of tumors as well as in TPA-induced skin tumors in mice. This study was undertaken to investigate the radiosensitizing effects of curcumin in p53 mutant prostate cancer cell line PC-3. Compared to cells that were irradiated alone (SF(2)=0.635; D(0)=231 cGy), curcumin at 2 and 4 microM concentrations in combination with radiation showed significant enhancement to radiation-induced clonogenic inhibition (SF(2)=0.224: D(0)=97 cGy and SF(2)=0.080: D(0)=38 cGy) and apoptosis. It has been reported that curcumin inhibits TNF-alpha-induced NFkappaB activity that is essential for Bcl-2 protein induction. In PC-3 cells, radiation upregulated TNF-alpha protein leading to an increase in NFkappaB activity resulting in the induction of Bcl-2 protein. However, curcumin in combination with radiation treated showed inhibition of TNF-alpha-mediated NFkappaB activity resulting in bcl-2 protein downregulation. Bax protein levels remained constant in these cells after radiation or curcumin plus radiation treatments. However, the downregulation of Bcl-2 and no changes in Bax protein levels in curcumin plus radiation-treated PC-3 cells, together, altered the Bcl2 : Bax ratio and this caused the enhanced radiosensitization effect. In addition, significant activation of cytochrome c and caspase-9 and -3 were observed in curcumin plus radiation treatments. Together, these mechanisms strongly suggest that the natural compound curcumin is a potent radiosesitizer, and it acts by overcoming the effects of radiation-induced prosurvival gene expression in prostate cancer.
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PMID:Curcumin confers radiosensitizing effect in prostate cancer cell line PC-3. 1498 1

Vascular injury is a major mechanism of cryosurgical destruction. The extent of vascular injury may be affected by the addition of molecular adjuvants. This study, in addition to determining the injury mechanism in the LNCaP Pro 5 human prostate cancer subline grown in a nude mouse, examined the effect of cytokine TNF-alpha on cryosurgery of an in vivo microvascular preparation (Dorsal Skin Flap Chamber). A comparison of injury data to a thermal model indicated that the minimum temperature after moderate cooling, thawing, and hold time required for causing necrosis was 3.5+/-6.9 degrees C in TNF-alpha-treated LNCaP Pro 5 tumor tissue (n=4) and -9.8+/-5.8 degrees C in TNF-alpha-treated normal skin of the nude mouse (n=4). Compared to tissues without TNF-alpha treatment, where the minimum temperature required for causing necrosis was -16.5+/-4.3 degrees C in LNCaP Pro 5 tumor tissue (n=8) and -24.4+/-7.0 degrees C in normal skin of the nude mouse (n=9), the results indicate the local use of TNF-alpha can dramatically increase the threshold temperature of cryo-destruction by more than 10 degrees C (p <0.01). These findings were consistent with the hypothesis that vascular-mediated injury is responsible for defining the edge of the cryolesion in microvascular-perfused tissue, and therefore pre-induced inflammation can augment cryoinjury. The local use of TNF-alpha to pre-inflame prostate cancer promises to increase both the ability of freezing to destroy cancer as well as improve the ability of ultrasound or other iceball-monitoring techniques to predict the outcome of the treatment.
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PMID:Pre-treatment inflammation induced by TNF-alpha augments cryosurgical injury on human prostate cancer. 1526 13

Enriched CD34(+) peripheral blood progenitor cells (PBPC) are frequently used as stem cell support in cancer patients following high dose therapy. Since precursor dendritic cells (DCs) originate from haematopoietic progenitor cells, purified CD34(+) cells might also serve as starting cells for ex- vivo production of DC. In the present study we developed a clinical grade procedure for ex- vivo production of DC derived from enriched CD34(+) cells. Different concentrations of CD34(+) cells were grown in gas-permeable Teflon bags with different serum-free and serum-containing media supplemented with GM-CSF, IL-4, TNF-alpha, SCF, Flt-3L and INF-alpha. Serum-free CellGroSCGM medium for 7 days followed by CellGroDC medium in 7 days gave the same results as serum-containing medium. After incubation the cultured cells containing immature DCs were concentrated and transfected with tumour mRNA from human prostate cancer cell lines employing a highly efficient electroporation procedure. Thawed transfected DCs were able to elicit primary T-cell responses in vitro against antigens encoded by the prostate cancer mRNA as shown by ELISPOT assay using mock-transfected DCs as control. Our results show that frozen enriched CD34(+) cells can be an alternative and efficient source for production of DCs for therapeutic purpose.
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PMID:Development of a clinical grade procedure for generation of mRNA transfected dendritic cells from purified frozen CD34(+) blood progenitor cells. 1546 59

The human prostatic carcinoma cell line DU145 has previously been found to be resistant to treatment with TNF-family ligands. However, TRAIL, TNF-alpha and anti-Fas antibodies (Ab) treatment in combination with the histone deacetylase inhibitor Trichostatin A (TSA) converted the phenotype of DU145 from resistant to sensitive. TSA induced 15% cell death but simultaneous treatment with TRAIL, TNF-alpha and anti-Fas Ab resulted in 55%, 70% and 40% cell death, respectively. Simultaneous treatment did not increase the level of TSA-induced histone acetylation, but induced the release of acetylated histones from chromatin into the cytosol. This release was caspase dependent since it was abrogated by Z-VAD-fmk. In addition, treatment with TSA induced caspase-9 activation and resulted in the release of cytochrome c and Smac/DIABLO from mitochondria. To further investigate the role of caspase-9 in TSA-mediated apoptosis we used two different approaches: (1) cells were pretreated with the caspase-9 inhibitor Z-LEHD-fmk, and (2) cells were transfected with a dominant-negative form of caspase-9. Both approaches gave similar results: cells became resistant to treatment with TSA. These data indicate that TSA mediates its effect via the mitochondrial pathway. This was confirmed by examining DU145 overexpressing Bcl-2. These transfectants were resistant to TSA treatment. Taken together, our data shows that only simultaneous treatment with TNF-family ligands and TSA in DU145 resulted in caspase activity sufficient to induce apoptosis. The combination of TSA and TNF-family ligands could potentially be the basis for the treatment of prostate cancer.
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PMID:Trichostatin A (TSA) sensitizes the human prostatic cancer cell line DU145 to death receptor ligands treatment. 1590


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