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 metabolism of arachidonic acid (AA) by either the cyclooxygenase (COX) or lipoxygenase (LOX) pathway generates eicosanoids, has been implicated in the pathogenesis of a variety of human diseases, including cancer, and may play important roles in tumor promotion, progression, and metastasis. The involvement of 12-LOX expression and function in tumor growth and metastasis has been reported in both murine and human tumor cell lines. The expression of 12-LOX in human renal cell carcinoma (RCC), normal kidney (NK) tissues and 3 kinds of RCC cell lines (Caki-1, A498, RC-1), and its effects on cell proliferation in 3 RCC cell lines were examined. Expression of 12-LOX protein was detected by immunohistochemistry and 12-LOX mRNA in RCC cell lines was detected by nested RT-PCR. Effects of 12-LOX inhibitor on RCC cell growth was examined by MTT assay, and to determine whether or not 12-LOX inhibitors induce apoptosis, we used Hoechst staining. While 12-LOX expression was detected slightly in NK tissues, a marked expression of 12-LOX was detected in RCC tissues. All human RCC cell lines expressed 12-LOX mRNA. The 12-LOX inhibitor baicalein caused marked inhibition of all three kinds of RCC cells in a concentration- and time-dependent manner. Cells treated with 12-LOX inhibitor showed chromatin condensation, cellular shrinkage, small membrane-bound bodies (apoptotic bodies), and cytoplasmic condensation. These results suggest 12-LOX may play a role in the progression of RCC in human tissue, and its inhibitors may become anticancer agents in human RCC.
Int J Mol Med 2004 Jan
PMID:Expression of 12-lipoxygenase in human renal cell carcinoma and growth prevention by its inhibitor. 1465 68

Apoptosis and necrosis are distinct forms of cell death that occur in response to various agents. We studied the action of N-Acetyl-D-sphingosine (C2-ceramide) or N-hexanoyl-D-sphingosine (C6-ceramide) in human hepatoma HepG2 cell line. The cells were treated in vitro for 1-24 h. Cell toxicity was evaluated by MTT assay. DNA content was estimated by gel electrophoresis and flow cytometry. Measurement of mitochondrial respiration, analysis of cytochrome c release and caspase-3 activation were assessed in order to determine if either of these events in the induction of apoptosis and/or necrosis was predominant. We have demonstrated that C2 and C6-ceramide were cytotoxic in a time and dose-dependent manner. After 24 h of treatment with 100 microM of C2 and C6 the morphology (May-Giemsa staining) of treated cells displayed an apoptotic phenotype in C6-treated cells, confirmed by a high (sub-G1 peak > 20%) proportion by flow cytometry while a necrotic morphology was observed after C2-ceramide treatment, confirmed by DNA smearing in DNA electrophoresis. After C6-ceramide incubation, the respiratory chain was functional only slightly inhibited (20%), there was production of ATP, cytochrome c release without ROS production, activation of caspase-3 and induction of apoptosis. On the contrary, C2-ceramide inhibited the respiratory chain more intensely (80%) increased significantly ROS production, which resulted in an arrest of ATP production, no cytochrome c release and absence of caspase-3 activation. Finally after complete exhaustion of intracellular ATP, mitochondrial explosion induced necrotic cell death. In conclusion, evidence suggest that mitochondrial respiratory chain function is essential for controlling the decision of the cell to enter a apoptotic or necrosis process.
Mol Cell Biochem 2003 Dec
PMID:Commitment to apoptosis by ceramides depends on mitochondrial respiratory function, cytochrome c release and caspase-3 activation in Hep-G2 cells. 1467 99

Arsenic is a naturally occurring element, but anthropogenic activities can lead to a substantial contamination of the environment. Exposure to arsenic has been associated with a significant number of adverse health effects in humans including: cardiovascular disease, diabetes, hearing loss, developmental abnormalities, anemia, neurologic and neurobehavioral disorder, leukopenia, eosinophilia, fibrosis of the liver and the kidney and various neoplasms. However, the cellular and molecular events associated with arsenic toxicity are poorly understood. Also, the precise mechanisms by which arsenic acts as a carcinogen in humans remain to be elucidated. In the present study, we used human liver carcinoma (HepG2) cells as a model to study the molecular mechanisms of arsenic-induced toxicity and carcinogenesis. We hypothesized that arsenic-induced expression of stress genes and related proteins may play a role in the cellular and molecular events leading to toxicity and tumorigenesis in liver cells. To test this hypothesis, we performed the MTT-assay for cell viability, the CAT-Tox (L) assay for gene induction, and the Western Blot analysis to assess the expression of cellular proteins including c-fos, HMTIIA, HSP70 and p53. Data obtained from the MTT assay indicated a strong dose-response relationship with respect to arsenic trioxide toxicity. Upon 48 hr of exposure, the chemical dose required to cause 50% reduction in cell viability (LD50) was computed to be 8.55 +/- 0.58 microg/ml. The CAT-Tox (L) assay showed statistically significant inductions (p<0.05) of c-fos, HMTIIA, and HSP70. Western blot analysis also demonstrated a dose-response relationship with regard to expression of specific cellular proteins. The p53 protein was expressed in arsenic trioxide-treated cells, however, the densitometric analysis did not show any significant differences (p<0.05) between treated and control cells. The lack of a significant induction of p53 may be due to the potential mitogenic effect of arsenic at low levels of arsenic exposure.
Cell Mol Biol (Noisy-le-grand) 2003 Nov
PMID:Arsenic trioxide-induced transcriptional activation of stress genes and expression of related proteins in human liver carcinoma cells (HepG2). 1468 89

Previous studies have shown that reduction in BRCA1 mRNA and protein can result in increased proliferation of BG-1 ovarian cancer cells in both in vitro and in vivo conditions, suggesting that BRCA1 may normally act as a growth inhibitor in these cells. Also, there are other reports that suggest that wild-type BRCA1 protein may repress estrogen receptor (ER) function either directly or indirectly. However, response to antiestrogen drugs in BRCA1-blocked ER-positive ovarian cancer cells has not been reported, and this served as the rationale for this study. We analyzed the effect of tamoxifen, emodin, and plumbagin in BRCA1-blocked ER-positive BG-1 ovarian cancer cells. For all three drugs, BRCA1-blocked cells were more sensitive than the corresponding control cells as assessed by MTT assay; however, only plumbagin showed a statistically significant difference in mean viability (P < 0.05). All three drugs induced loss of mitochondrial membrane potential (DeltaPsi(m)), nuclear condensation, DNA fragmentation, and morphological changes, as observed after 6 h of drug treatment, suggesting apoptosis induction in both BRCA1-blocked and control cells. However, apoptosis induction was greater in BRCA1-blocked cells, the efficacy being in the order of plumbagin > tamoxifen > emodin. The dose of plumbagin needed to kill 50% was 5 microM in the control cells and 2.68 microM for the BRCA1-blocked cells, indicating that the latter was about twofold more sensitive to plumbagin than the wild-type cells. This throws light on the fact that plumbagin may have chemotherapeutic potential as an anticancer agent in BRCA1-mutated ovarian cancer patients.
Mol Carcinog 2004 Jan
PMID:Antisense blocking of BRCA1 enhances sensitivity to plumbagin but not tamoxifen in BG-1 ovarian cancer cells. 1469 44

Non-aromatizable androgens have significant beneficial effects on skeletal homeostasis independently of conversion to estradiol, but the effects of androgens on bone cell metabolism and cell proliferation are still poorly understood. Using an osteoblastic model with enhanced androgen responsiveness, MC3T3-E1 cells stably transfected with androgen receptor (AR) under the control of the type I collagen promoter (colAR-MC3T3), the effects of androgens on mitogenic signaling were characterized. Cultures were treated with the non-aromatizable androgen 5alpha-dihydrotestosterone (DHT) and the effects on osteoblast viability were determined as measured by an MTT assay. A complex response was observed in that continuous short-term DHT treatment enhanced osteoblast viability, but with longer-term DHT treatment inhibition was observed. The inhibition by DHT was prevented by the specific AR antagonist hydroxyflutamide, and was also observed in primary cultures of normal rat calvarial osteoblasts. In order to identify potential mediators of this effect, mitogenic pathway-specific cDNA microarrays were interrogated. Reduced hybridization of several genes important in MAP kinase-mediated signaling was observed, with the most dramatic effect on Elk-1 expression. Analysis of phosphorylation cascades demonstrated that DHT treatment inhibited phosphoERK1/2 levels, MAP kinase activation of Elk-1, Elk-1 protein and phosphoElk-1 levels, and downstream AP-1/luciferase reporter activity. Together, these data provide the first evidence that androgen inhibition of the MAP kinase signaling pathway is a potential mediator of osteoblast growth, and are consistent with the hypothesis that the MAP cascade may be a specific downstream target of DHT.
J Mol Endocrinol 2004 Feb
PMID:Androgen inhibition of MAP kinase pathway and Elk-1 activation in proliferating osteoblasts. 1476 3

The metabolism of arachidonic acid by either the cyclooxygenase (COX) or lipoxygenase (LOX) pathway generates eicosanoids, which have been implicated in the pathogenesis of a variety of human diseases, including cancer. They are now believed to play important roles in tumor promotion, progression, and metastasis, and the involvement of LOX expression and function in tumor growth and metastasis has been reported in human tumor cell lines. Expressions of 5-LOX and 12-LOX in human testicular cancer (TC), and normal testis (NT) tissues were examined, as well as effects of their inhibitors on cell proliferation in TC cell line. Expressions of 5-LOX and 12-LOX were detected by immunohistochemistry. Effects of LOX inhibitors on TC cell growth were examined by MTT assay. While 5-LOX and 12-LOX expressions were slightly detected in NT tissues, expressions of 5-LOX and 12-LOX were significant detected in TC tissues by immunohistochemistry. The LOX inhibitors inhibited the growth of TC cells. LOX is induced in TC, and results may suggest that LOXs are essential for cell growth of TC cells.
Int J Mol Med 2004 Mar
PMID:Relationship between lipoxygenase and human testicular cancer. 1476 68

The aim of this study is to investigate whether homocysteine (Hcy) has influences on endothelial progenitor cells (EPCs) number and activity. Total mononuclear cells (MNCs) were isolated from peripheral blood by Ficoll density gradient centrifugation, and then the cells were plated on fibronectin-coated culture dishes. After 7 d cultured, attached cells were stimulated with Hcy (to make a series of final concentrations: 10, 50, 100 and 200 micromol/l) or vehicle control for the respective time points (6, 12, 24 and 48 h). EPCs were characterized as adherent cells double positive for DiLDL uptake and lectin binding by direct fluorescent staining under a laser scanning confocal microscope. EPCs proliferation, migration and in vitro vasculogenesis activity were assayed with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, modified Boyden chamber assay and in vitro vasculogenesis kit, respectively. EPCs adhesion assay was performed by replating those on fibronectin-coated dishes, and then adherent cells were counted. Incubation of isolated human MNCs with Hcy dose and time dependently decreased the number of EPCs, maximum at 200 micromol/l, 24 h (approximately 50% reduction, P < 0.01). In addition, Hcy dose and time dependently impaired EPC proliferative, migratory, adhesive and in vitro vasculogenesis capacity. In conclusion, hyperHcy may induce the reduction of EPCs with decreased functional activity.
J Mol Cell Cardiol 2004 Feb
PMID:Effects of homocysteine on number and activity of endothelial progenitor cells from peripheral blood. 1487 51

Lead is a non-essential element that exhibits a high degree of toxicity, especially in children. Most research on lead has focused on its effects on organ systems such as the nervous system, the red blood cells, and the kidneys which are considered to be the primary targets of lead toxicity. However, the molecular mechanisms by which it induces toxicity, and carcinogenesis remain to be elucidated. In this research, we performed the MTT assay to assess the cytotoxicity, and the CAT-Tox assay to assess the transcriptional responses associated with lead exposure to thirteen different recombinant cell lines generated from human liver carcinoma cells (HepG2), by creating stable transfectants of mammalian promoter chloramphenicol (CAT) gene fusions. Study results indicated that lead nitrate is cytotoxic to HepG2 cells, showing LD50 values of 49.0 +/- 18.0 microg/mL, 37.5 +/- 9.2 microg/mL, and 3.5 +/- 0.7 microg/mL for cell mortality upon 24, 48 and 72 h of exposure, respectively; indicating a dose- and time-dependent response with regard to the cytotoxic effect of lead nitrate. A dose-response relationship was also recorded with respect to the induction of stress genes in HepG2 cells exposed to lead nitrate. Overall, six out of the thirteen recombinant cell lines tested showed inductions to statistically significant levels (p < 0.05). At 50 microg/mL of lead nitrate, the average fold inductions were: 2.1 +/- 1.0, 5.4 +/- 0.4, 12.1 +/- 6.2, 5.0 +/- 1.7, 2.5 +/- 1.3, and 4.8 +/- 4.5 for XRE, HSP70, CRE, GADD153, and GRP78, respectively. These results indicate the potential for lead nitrate to undergo biotransformation in the liver (XRE), to cause cell proliferation (c-fos), protein damage (HSP70, GRP78), metabolic perturbation (CRE), and growth arrest and DNA damage (GADD153). Marginal but not significant inductions were also obtained with the GSTYa (1.5 +/- 0.8), and GADD45 (5.7 +/- 8.1) promoters, and the NF-KB (2.0 +/- 1.7) response element, indicating the potential for oxidative stress. No significant inductions (p > 0.05) were recorded for CYP1A1, HMTIIA, p53RE, and RARE.
Mol Cell Biochem 2004 Jan
PMID:Lead-induced cytotoxicity and transcriptional activation of stress genes in human liver carcinoma (HepG2) cells. 1497 57

Recent studies have demonstrated that lipoxygenase (LOX) inhibitor induces growth arrest of cancer cells through apoptosis. In this study, we examined the effects of LOX inhibitors on cell proliferation in renal cell carcinoma (RCC), bladder tumor (BT), and prostate cancer (PC) cell lines. We investigated the inhibitory effect of LOX inhibitors, 5-, 12- and non-specific LOX inhibitor on RCC, BT and PC-derived cell lines using MTT assay and Hoechst staining. All LOX inhibitors induced the reduction of cell viability with the half-maximal concentration of growth inhibition of RCC, BT, and PC cell lines. Furthermore, counting cells at days 1, 2 and 3, clearly showed marked inhibition of cell proliferation by treatment with non-specific and 5-LOX inhibitor. All LOX inhibitors stopped the growth of all RCC, BT and PC cells. The effect of non-specific LOX inhibitor was strongest. The effect of 5-LOX inhibitor was stronger than 12-LOX inhibitor. All LOX inhibitors caused marked inhibition of urological cancer cells through apoptosis. LOX inhibitor may mediate potent antiproliferative effects against RCC, BT and PC cells through differentiation. Thus, LOX inhibitor, especially 5-LOX inhibitor may become a new target in treatment of urological cancers.
Int J Mol Med 2004 May
PMID:Lipoxygenase inhibitors prevent urological cancer cell growth. 1506 67

Cyclooxygenase (COX)-2 plays an important role in the development of various cancers due to its angiogenic function. We have demonstrated that the expression of COX-2 was up-regulated in human renal cell carcinoma (RCC), bladder tumor (BT) and prostate cancer (PC). In this study, we examined the effects of COX-2 inhibitors on cell proliferation in RCC, BT and PC-derived cell lines using MTT assay and Hoechst staining. COX-2 inhibitors did not induce a reduction of cell viability with the half-maximal concentration of growth inhibition of RCC, BT and PC cell lines. Furthermore, counting cells at days 1, 2 and 3, showed no inhibition of cell proliferation using COX-2 inhibitors. COX-2 inhibitors could not stop the growth of RCC, BT and PC cells. Typical characteristics of apoptosis, i.e. chromatin condensation, cellular shrinkage, small membrane-bound bodies (apoptotic bodies) and cytoplasmic condensation, did not occur. Although the expression of COX-2 was up-regulated in human RCC, BT and PC tissues, COX-2 inhibitors have only slight anti-proliferative effects against RCC, BT and PC cells through differentiation. Thus, using only down-regulation of arachidonic acid (AA) metabolizing enzyme, COX may be an unsuccessful approach in providing new anti-cancer therapies.
Int J Mol Med 2004 Jun
PMID:The effects of cyclooxygenase-2 inhibitors on urological cancer cells. 1513 13


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