Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The recent discovery of sodium (Na(+)) channel expression in human prostate cancer (PCa) cells led us to investigate the potential use of neuronal Na(+) channel blockers as inhibitors of PCa cells. Our initial studies discovered two classes of Na(+) channel blockers that were effective inhibitors of PCa cell proliferation. Both hydroxyamides (compounds 1 and 4) and a hydantoin (compound 5) were shown to inhibit the androgen-independent PCa cell line PC-3 in vitro. Electrophysiology showed that all compounds functionally block brain type II voltage-gated Na(+) channels (Nav1.2) expressed in Xenopus laevis oocytes. Long-term growth assays in androgen-independent PC-3 cells showed remarkable inhibition of cell growth, with cells growing to a maximum of 30% of controls with analogue 1. Further, our analogues demonstrated only marginal impact on cell viability over the same treatment interval.
Mol Cancer Ther 2003 Nov
PMID:Voltage-gated sodium channel blockers as cytostatic inhibitors of the androgen-independent prostate cancer cell line PC-3. 1461 88

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.
Cell Mol Biol (Noisy-le-grand) 2003 Nov
PMID:Activated eosinophils upregulate the metastasis suppressor molecule E-cadherin on prostate tumor cells. 1468 82

A bioenergetic theory of prostate malignancy proposed that normal citrate-producing prostate epithelial cell become citrate-oxidizing cells, in which mitochondrial aconitase (mACON) is not limiting, providing the energy required for the onset and progression of malignancy and metastasis. However, no direct evidence has been approved to support the hypothesis. A full-length cDNA encoding human skeletal muscle mACON cDNA was cloned and sequenced. mACON cDNA contains 19-bp 5' untranslated region, a 2343-bp coding segment, and 376-bp 3' untranslated region. This precursor enzyme contains mitochondrial targeting sequence of 27 amino acid residues and mature enzyme of 753 amino acids residues. A human anti-mACON overexpression vector containing the 1171-bp mACON cDNA fragment in the reverse orientation was stable transfected into human prostate carcinoma cells, PC-3 and DU145 cells. Results showed that mACON antisense blocked 40-60% mACON expression and enzymatic activity which induced decrease in the intracellular ATP biosynthesis but increase citrate secretion in the human prostate carcinoma cells. mACON antisense-transfected cells have lower cell proliferation ratio than the mock of DNA-transfected cells. Our study demonstrated the key role of the mACON in the cellular bioenergy and cell proliferation of human prostate carcinoma cells.
Mol Genet Metab 2004 Mar
PMID:Modulation of mitochondrial aconitase on the bioenergy of human prostate carcinoma cells. 1497 31

The hypoxia-inducible factor-1 (HIF-1) transcription factor is an important regulator of tumor response to hypoxia that include increased angiogenesis, glycolytic metabolism, and resistance to apoptosis. HIF-1 activity is regulated by the availability of the HIF-1alpha subunit, the levels of which increase under hypoxic conditions. PX-478 (S-2-amino-3-[4'-N,N,-bis(2-chloroethyl)amino]phenyl propionic acid N-oxide dihydrochloride) is an inhibitor of constitutive and hypoxia-induced HIF-1alpha levels and thus HIF-1 activity. We report that PX-478 given to mice suppresses HIF-1alpha levels in HT-29 human colon cancer xenografts and inhibits the expression of HIF-1 target genes including vascular endothelial growth factor and the glucose transporter-1. PX-478 shows antitumor activity against established (0.15-0.40 cm(3)) human tumor xenografts with cures of SHP-77 small cell lung cancer and log cell kills up to 3.0 for other tumors including HT-29 colon, PC-3 prostate, DU-145 prostate, MCF-7 breast, Caki-1 renal, and Panc-1 pancreatic cancers. Large (0.83 cm(3)) PC-3 prostate tumors showed 64% regression, which was greater than for smaller tumors. The antitumor response to PX-478 was positively correlated with tumor HIF-1alpha levels (P < 0.02) and was accompanied by massive apoptosis. The results show that PX-478 is an inhibitor of HIF-1alpha and HIF-1 transcription factor activity in human tumor xenografts and has marked antitumor activity against even large tumor xenografts, which correlates positively with HIF-1alpha levels.
Mol Cancer Ther 2004 Mar
PMID:Antitumor activity and pharmacodynamic properties of PX-478, an inhibitor of hypoxia-inducible factor-1alpha. 1502 44

Phenethyl isothiocyanate (PEITC), a constituent of many cruciferous vegetables, offers significant protection against cancer in animals induced by a variety of carcinogens. The present study demonstrates that PEITC suppresses proliferation of PC-3 cells in a dose-dependent manner by causing G(2)-M-phase cell cycle arrest and apoptosis. Interestingly, phenyl isothiocyanate (PITC), which is a structural analogue of PEITC but lacks the -CH(2) spacers that link the aromatic ring to the -N=C=S group, neither inhibited PC-3 cell viability nor caused cell cycle arrest or apoptosis. These results indicated that even a subtle change in isothiocyanate (ITC) structure could have a significant impact on its biological activity. The PEITC-induced cell cycle arrest was associated with a >80% reduction in the protein levels of cyclin-dependent kinase 1 (Cdk1) and cell division cycle 25C (Cdc25C; 24 h after treatment with 10 micro M PEITC), which led to an accumulation of Tyr(15) phosphorylated (inactive) Cdk1. On the other hand, PITC treatment neither reduced protein levels of Cdk1 or Cdc25C nor affected Cdk1 phosphorylation. The PEITC-induced decline in Cdk1 and Cdc25C protein levels and cell cycle arrest were significantly blocked on pretreatment of PC-3 cells with proteasome inhibitor lactacystin. A 24 h exposure of PC-3 cells to 10 micro M PEITC, but not PITC, resulted in about 56% and 44% decrease in the levels of antiapoptotic proteins Bcl-2 and Bcl-X(L), respectively. However, ectopic expression of Bcl-2 failed to alter sensitivity of PC-3 cells to growth inhibition or apoptosis induction by PEITC. Treatment of cells with PEITC, but not PITC, also resulted in cleavage of procaspase-3, procaspase-9, and procaspase-8. Moreover, the PEITC-induced apoptosis was significantly attenuated in the presence of general caspase inhibitor and specific inhibitors of caspase-8 and caspase-9. In conclusion, our data indicate that PEITC-induced cell cycle arrest in PC-3 cells is likely due to proteasome-mediated degradation of Cdc25C and Cdk1, and ectopic expression of Bcl-2 fails to confer resistance to PEITC-induced apoptosis. Furthermore, the results of the present study point toward involvement of both caspase-8- and caspase-9-mediated pathways in apoptosis induction by PEITC.
Mol Cancer Ther 2004 May
PMID:Proteasome-mediated degradation of cell division cycle 25C and cyclin-dependent kinase 1 in phenethyl isothiocyanate-induced G2-M-phase cell cycle arrest in PC-3 human prostate cancer cells. 1514 Oct 14

Mitochondrial aconitase (mACON) is regarded as the key enzyme for citrate oxidation in human prostatic epithelial cells. The results of RT-PCR and immunoblot assays indicated that human prostatic carcinoma cells (PC-3 cells) express the long-form of the prolactin receptor. In vitro studies determined that prolactin upregulates mACON enzymatic activity and cell proliferation of PC-3 cells. Immunoblot assay revealed that prolactin treatments increase the gene expression of mACON. Transient gene expression assay indicated that the regulation by prolactin of mACON gene expression depends on the presence of the cyclic adenosine 3',5'-monosphosphate (cAMP) response element on the promoter of the mACON gene. Both prolactin and dibutyryl-cAMP doubled the promoter activity of the mACON gene; however, adding H-89, a specific protein kinase A inhibitor, suppressed the prolactin response. The intracellular cAMP levels, but not the cGMP levels, increased after treatment with prolactin. This study showed that prolactin regulates the expression of the mACON gene via the cAMP signal pathway in human prostatic carcinoma cells.
Mol Cell Endocrinol 2004 Apr 30
PMID:Cyclic adenosine 3',5'-monosphosphate mediate prolactin regulation of mitochondrial aconitase in human prostate carcinoma cells. 1514 35

Aminoflavone (4H-1-benzopyran-4-one, 5-amino-2-(4-amino-3-fluorophenyl)-6,8-difluoro-7-methyl; NSC 686288) demonstrates differential antiproliferative activity in the National Cancer Institute's anticancer drug screen. We demonstrate here that MCF-7 human breast cancer cells are sensitive to aminoflavone both in vitro and when grown in vivo as xenografts in athymic mice. As previous work has indicated that aminoflavone requires metabolic activation by cytochrome P450 1A1 (CYP1A1), we investigated the effect of aminoflavone on CYP1A1 expression and on the aryl hydrocarbon receptor (AhR), a transcriptional regulator of CYP1A1. In aminoflavone-sensitive but not aminoflavone-resistant cells, the drug caused a 100-fold induction of CYP1A1 mRNA and a corresponding increase in ethoxyresorufin-O-deethylase activity. An AhR-deficient variant of the MCF-7 breast carcinoma, AH(R100), with diminished CYP1A1 inducibility, exhibits cellular resistance to aminoflavone and is refractory to CYP1A1 mRNA induction by the drug. The increase in CYP1A1 mRNA in the aminoflavone-sensitive MCF-7 breast tumor cell results from transcriptional activation of xenobiotic-responsive element (XRE)-controlled transcription. Aminoflavone treatment causes a translocation of the AhR from the cytoplasm to the nucleus with subsequent formation of AhR-XRE protein DNA complexes. In contrast to the aminoflavone-sensitive MCF-7 cells, the resistant cell lines (MDA-MB-435, PC-3, and AH(R100)) demonstrated constitutive nuclear localization of AhR. Additionally, aminoflavone failed to induce ethoxyresorufin-O-deethylase activity, CYP1A1 transcription, AhR-XRE complex formation, and apoptosis in aminoflavone-resistant cells. These results suggest that the cytotoxicity of aminoflavone in a sensitive breast tumor cell line is the result of the engagement of AhR-mediated signal transduction.
Mol Cancer Ther 2004 Jun
PMID:Aryl hydrocarbon receptor activation of an antitumor aminoflavone: basis of selective toxicity for MCF-7 breast tumor cells. 1521 Aug 58

Accumulating data suggest that local production of 1alpha,25-dihydroxyvitamin D (1alpha,25(OH)(2)D) could provide an important cell growth regulatory mechanism in an autocrine fashion in prostate cells. Previously, we demonstrated a differential expression of 1alpha-OHase enzymatic activity among noncancerous (PZHPV-7) and cancer cells (PC-3, DU145, LNCaP), which appears to correlate with 1alpha-OHase m-RNA synthesis and its promoter activities. Since it is well-established that EGF regulates the proliferation of prostate cells via autocrine and paracrine loops and 1alpha,25(OH)(2)D inhibites prostate cell proliferation, we investigated if EGF also regulated 1alpha-OHase expression in prostate cells. We found that EGF upregulated 1alpha-OHase promoter activity and enzyme activity in PZ-HPV-7 and that 1alpha,25(OH)(2)D(3) inhibited EGF-dependent up-regulation of 1alpha-OHase enzymatic activity. Moreover, the EGF-stimulated promoter activity was inhibited 70% by the MAPKK inhibitor, PD98059, suggesting that the MAPK pathway may be one pathway involved in the regulation of prostatic 1alpha-OHase by EGF to increase1alpha,25(OH)(2)D synthesis as a feedback regulator of cell growth. Because EGF has no effect on 1alpha-OHase promoter activity in LNCaP cells, we propose that the ability of EGF to stimulate 1alpha,25(OH)(2)D synthesis may be abolished or diminished in cancer cells.
J Steroid Biochem Mol Biol 2004 May
PMID:Regulation of 25-hydroxyvitamin D-1alpha-hydroxylase by epidermal growth factor in prostate cells. 1522 59

Cdc25A and Cdc25B dual-specificity phosphatases are key regulators of cell cycle transition and proliferation. They have oncogenic properties and are overexpressed in many human tumors. Because selective Cdc25 phosphatase inhibitors would be valuable biological tools and possible therapeutic agents, we have assayed a small molecule library for in vitro inhibition of Cdc25. We now report the identification of two new structurally distinct classes of Cdc25 inhibitors with cellular activity. The cyclopentaquinoline 3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-4,8-dicarboxylic acid (5661118) and the naphthofurandione 3-benzoyl-naphtho[1,2-b]furan-4,5-dione (5169131) had in vitro IC50 values of 2.5 to 11 microM against recombinant Cdc25 and were less potent inhibitors of other phosphatases. Unlike 5661118, 5169131 caused reversible inhibition of Cdc25B and displayed competitive inhibitor kinetics. No growth inhibitory activity was seen with 5661118, whereas 10 to 30 microM 5169131 caused G1/S and G2/M arrest. We also found that 5169131 inhibited human PC-3 prostate and MDA-MB-435 breast cancer cell proliferation. Concentration-dependent Tyr15 hyperphosphorylation was seen on cyclin-dependent kinase with a 1-h 5169131 treatment, consistent with Cdc25 inhibition. Cells resistant to DNA toposiomerase II inhibitors were as sensitive to 5169131 as parental cells, indicating that this quinone compound does not inhibit topoisomerase II in vivo. Molecular modeling was used to predict a potential interaction site between the inhibitor and Cdc25B and to provide insights as to the molecular origins of the experimental observations. Based on its kinetic profile and cellular activity, we suggest that 5169131 could be an excellent tool for further studies on the cellular roles of Cdc25.
Mol Pharmacol 2004 Oct
PMID:Discovery and characterization of novel small molecule inhibitors of human Cdc25B dual specificity phosphatase. 1523 69

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a highly promising candidate for the treatment of cancer because it elicits cell death in the majority of tumor cells while sparing most normal cells. Some cancers, however, display resistance to TRAIL, suggesting that treatment with TRAIL alone may be insufficient for cancer therapy. In the present study, we explored whether the apoptotic responsiveness of PC-3 prostate cancer cells to TRAIL could be enhanced by targeting the novel protein kinase C (PKC) isoform eta. Transfection of PC-3 cells with second-generation chimeric antisense oligonucleotides against PKCeta caused a time- and dose-dependent knockdown of PKCeta, as revealed by real-time RT-PCR and Western blot analyses. Knockdown of PKCeta resulted in a marked amplification of TRAIL's cytotoxic activity. Cell killing could be substantially prevented by the pan-caspase inhibitor z-VAD-fmk. In addition, PKCeta knockdown and administration of TRAIL significantly synergized in activation of caspase-3 and internucleosomal DNA fragmentation. Knockdown of PKCeta augmented TRAIL-induced dissipation of the mitochondrial transmembrane potential and release of cytochrome c from mitochondria into the cytosol, indicating that PKCeta acts upstream of mitochondria. We conclude that PKCeta represents a considerable resistance factor with respect to TRAIL and a promising target to exploit the therapeutic potential of TRAIL.
Mol Cancer Ther 2004 Jul
PMID:Down-regulation of protein kinase Ceta potentiates the cytotoxic effects of exogenous tumor necrosis factor-related apoptosis-inducing ligand in PC-3 prostate cancer cells. 1525 38


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