Biomedical subjects

X Xu

Publications and source records attributed to X Xu.

At least 109 records · Page 6Linked to original sources

PubMed2001

p21-activated kinase-1 (PAK1) inhibition of the human scavenger receptor class B, type I promoter in macrophages is independent of PAK1 kinase activity, but requires the GTPase-binding domain.

Scavenger receptor class B, type I (SR-BI), is a high density lipoprotein receptor that mediates the flux of cholesterol between high density lipoprotein and cells. Recent evidence suggests that SR-BI plays a role in atherosclerosis and that inflammatory mediators down-regulate SR-BI in the macrophage. The purpose of this study was to evaluate the ability of lipopolysaccharide (LPS) to down-regulate the activity of the human SR-BI promoter in the macrophage and to delineate the mechanisms involved. Experiments with cultured cells and in vivo derived macrophages showed that LPS has a powerful suppressive effect on SR-BI expression both in vitro and in vivo. Transient transfection studies demonstrated that LPS represses SR-BI promoter activity in the macrophage cell line RAW 264.7. Cotransfection with either a constitutively active p21-activated protein kinase-1 (PAK1) construct (T423E) or a kinase-deficient PAK1 construct (K299R) resulted in repression of the SR-BI promoter, similar to LPS. These results demonstrate that PAK1-mediated down-regulation of the SR-BI promoter is independent of PAK1 kinase activity and suggest that PAK1 mediates the LPS-induced decrease in promoter activity. Cotransfection with constitutively active Cdc42 or Rac expression constructs also resulted in down-regulation of the promoter; whereas the dominant-negative Cdc42 and Rac constructs elevated basal promoter activity and blunted the LPS response. Cotransfection of PAK1 constructs containing mutations in both the kinase domain and the Cdc42/Rac-binding domain attenuated the PAK1-mediated down-regulation of the promoter, suggesting that Rac and Cdc42 are required for PAK1-mediated decreases in SR-BI promoter activity. 5'-Deletion analysis and gel shift data suggest that LPS inhibits binding of a novel transcription factor to a myeloid zing finger protein-1-like element (-476 to -456) in the human SR-BI promoter. These results demonstrate that the PAK1 pathway down-regulates the SR-BI promoter and suggest that activation of this pathway may play an important role in cholesterol trafficking in the vessel wall.

Animals↗

PubMed2001

Expression of multiple larger-sized transcripts for several genes in oligodendrogliomas: potential markers for glioma subtype.

Astrocytomas and oligodendrogliomas are two brain tumors that follow different clinical courses. Although many of these tumors can be identified based on standard histopathological criteria, a significant percentage present notable problems in diagnosis. To identify markers that might prove useful in distinguishing glioma subtypes, we prepared and analyzed cDNA libraries for differential expression of genes in an astrocytoma (grade II), an oligodendroglioma (grade II), and a meningioma (benign). The tumor libraries were compared by sequencing randomly selected clones and tabulating the expression frequency of each gene. In addition to identifying several genes previously reported or expected to be differentially expressed among these tumors, several potential new brain tumor markers were identified and confirmed by Northern blot analysis of a panel of brain tumors. A surprising result of this analysis was the observation that several larger-sized transcripts for various genes were predominantly expressed in the oligodendroglioma tumors, when compared to the other brain tumors or in non-tumor gray matter. These findings are consistent with different pre-mRNA splicing patterns observed between oligodendrogliomas and astrocytomas. In support of this hypothesis, our screen revealed significantly higher levels of two hnRNP A1 transcripts in oligodendrogliomas. hnRNP A1 is a component of the spliceosome whose expression levels affect splice site selection in vivo. The preferential expression of larger-sized transcripts for several genes in oligodendrogliomas may be useful for distinguishing astrocytic and oligodendroglial gliomas.

Astrocytoma↗

PubMed2001

Exposure-response relationship between paternal smoking and children's pulmonary function.

We conducted a cross-sectional study to investigate paternal smoking and children's pulmonary function in rural communities of Anqing, China. Our analysis included 1,718 children 8 to 15 yr of age whose mothers were never-smokers. Multiple linear regression models were used to estimate the effect of paternal smoking on children's pulmonary function, with adjustment for children's age, sex, weight, height, square of height, asthma, and father's education. When compared with children of never-smoking fathers, children of smoking fathers had small, but detectable deficits in FEV(1) (-36 ml, SE = 20) and FVC (-37 ml, SE = 22). When children of smoking fathers were subdivided into two subgroups, father smoked < 30 cigarettes/day and >/= 30 cigarettes/day, we found that children whose fathers smoked >/= 30 cigarettes/day had the largest deficits in both FEV(1) (-79 ml, SE = 30) and FVC (-71 ml, SE = 34). This monotonic exposure-response relationship remained in all strata when we further stratified our analysis by children's sex and asthma status. Our data also suggested that the relationship was greatest among nonasthmatic girls, although neither sex nor asthma interaction terms were statistically significant. We conclude that there is a monotonic exposure-response relationship between paternal smoking and decline of pulmonary function in children in this rural Chinese population.

Adolescent↗

PubMed2001

Inhibition of DNA replication and induction of S phase cell cycle arrest by G-rich oligonucleotides.

The discovery of G-rich oligonucleotides (GROs) that have non-antisense antiproliferative activity against a number of cancer cell lines has been recently described. This biological activity of GROs was found to be associated with their ability to form stable G-quartet-containing structures and their binding to a specific cellular protein, most likely nucleolin (Bates, P. J., Kahlon, J. B., Thomas, S. D., Trent, J. O., and Miller, D. M. (1999) J. Biol. Chem. 274, 26369-26377). In this report, we further investigate the novel mechanism of GRO activity by examining their effects on cell cycle progression and on nucleic acid and protein biosynthesis. Cell cycle analysis of several tumor cell lines showed that cells accumulate in S phase in response to treatment with an active GRO. Analysis of 5-bromodeoxyuridine incorporation by these cells indicated the absence of de novo DNA synthesis, suggesting an arrest of the cell cycle predominantly in S phase. At the same time point, RNA and protein synthesis were found to be ongoing, indicating that arrest of DNA replication is a primary event in GRO-mediated inhibition of proliferation. This specific blockade of DNA replication eventually resulted in altered cell morphology and induction of apoptosis. To characterize further GRO-mediated inhibition of DNA replication, we used an in vitro assay based on replication of SV40 DNA. GROs were found to be capable of inhibiting DNA replication in the in vitro assay, and this activity was correlated to their antiproliferative effects. Furthermore, the effect of GROs on DNA replication in this assay was related to their inhibition of SV40 large T antigen helicase activity. The data presented suggest that the antiproliferative activity of GROs is a direct result of their inhibition of DNA replication, which may result from modulation of a replicative helicase activity.

Apoptosis↗

PubMed2001

[Defective expression of B7.2 in B cell chronic lymphocytic leukemia B cells].

OBJECTIVE: To investigate the expression of B7.1 and B7.2 molecules in peripheral B cells of patients with chronic B cell lymphocytic leukemia (BCLL) and to study the relationship between B7.1 and B7.2 expression and pathogenic mechanism of BCLL. METHODS: Peripheral blood mononuclear cells (PBMC) were separated by Ficoll-Hypaque lymphocytes separation medium from 25 normal persons (normal control group) and 23 BCLL patients (BCLL group) which were further divided into two groups, phase 0-II group and phase III-IV group. Flow cytometry (FCM) was used to analyze the B7.1 and B7.2 expression in peripheral B cells after the mononuclear cells had been cultured for 24 hours in vitro. RESULTS: The B7.2 expression in B cells of BCLL patients was significantly lower than that in normal control group (P < 0.05). No statistically significant difference was found in the B7.1 expression and co-expression of B7.1 and B7.2 between the BCLL group and normal control group. The average B7.2 expression rates in patients of phase 0-II group and phase III-IV group were 25% +/- 17% and 17% +/- 8% respectively without statistically significant difference. CONCLUSION: The B7.2 expression in B cell of patients with BCLL is defective, which may be one of the pathogenic mechanisms of chronic BCLL and a major cause why the body fails to clear the BCLL cells via immunological means.

Adult↗

PubMed2001

Antibody catalysis of the oxidation of water.

Recently we reported that antibodies can generate hydrogen peroxide (H2O2) from singlet molecular oxygen (1O2*). We now show that this process is catalytic, and we identify the electron source for a quasi-unlimited generation of H2O2. Antibodies produce up to 500 mole equivalents of H2O2 from 1O2*, without a reduction in rate, and we have excluded metals or Cl- as the electron source. On the basis of isotope incorporation experiments and kinetic data, we propose that antibodies use H2O as an electron source, facilitating its addition to 1O2* to form H2O3 as the first intermediate in a reaction cascade that eventually leads to H2O2. X-ray crystallographic studies with xenon point to putative conserved oxygen binding sites within the antibody fold where this chemistry could be initiated. Our findings suggest a protective function of immunoglobulins against 1O2* and raise the question of whether the need to detoxify 1O2* has played a decisive role in the evolution of the immunoglobulin fold.

Animals↗

PubMed2001

Regulation of cAMP-responsive element-binding protein-mediated transcription by the SNF2/SWI-related protein, SRCAP.

SRCAP (SNF2-related CPB activator protein) belongs to the SNF2 family of proteins whose members participate in various aspects of transcriptional regulation, including chromatin remodeling. It was identified by its ability to bind to cAMP-responsive-binding protein (CREB)-binding protein (CBP), and it increases the transactivation function of CBP. The phosphoenolpyruvate carboxykinase (PEPCK) promoter was used as a model system to explore the role of SRCAP in the regulation of transcription mediated by factors that utilize CBP as a coactivator. We show that transcription of a PEPCK chloramphenicol acetyltransferase (CAT) reporter gene activated by protein kinase A (PKA) is enhanced 7-fold by SRCAP. In the absence of PKA this SRCAP-mediated enhancement does not occur, suggesting that SRCAP functions as a coactivator for PKA-activated factors such as CREB. Replacing the PEPCK promoter binding site for CREB with a binding site for Gal4 (DeltaCRE (cAMP-responsive element) Gal4 PEPCK-CAT reporter gene) blocks the ability of SRCAP to activate transcription despite the presence of PKA. Expression of a Gal-CREB chimera restores the ability of PKA to regulate transcription of the DeltaCRE Gal4 PEPCK gene and restored the ability of SRCAP to stimulate PKA-activated transcription. In addition, SRCAP in the presence of PKA enhances the ability of the Gal-CREB chimera to activate transcription of a Gal-CAT reporter gene that contains only binding sites for Gal4. SRCAP binds to CBP amino acids 280-460, a region that is important for CBP to function as a coactivator for CREB. Overexpression of a SRCAP peptide corresponding to this CBP binding domain acts as a dominant negative inhibitor of CREB-mediated transcription. Structure-function studies were done to explore the mechanism(s) by which SRCAP regulates transcription. These studies indicate that the N-terminal region of SRCAP, which contains five of the seven regions that comprise the ATPase domain, is not needed for activation of CREB-mediated transcription. SRCAP apparently has several domains that participate in the activation of transcription.

Adenosine Triphosphatases↗

PubMed2001

The analysis of heparin-protein interactions using evanescent wave biosensor with regioselectively desulfated heparins as the ligands.

Evanescent wave biosensor has been recently employed as a powerful tool for analyses of macromolecular interactions. In the present study, evanescent wave biosensor analysis was developed to analyze the heparin-protein interaction using as ligands a series of heparin derivatives regioselectively desulfated by chemical methods, particularly to evaluate the effect of each sulfate group of heparin. The method for immobilizing heparin on the cuvette of the evanescent wave biosensor equipment was optimized to obtain the high response required for accurate measurement. The best result was achieved when the amino group introduced at the reducing end of heparin was coupled with carboxymethyl dextran on the surface of the cuvette using glycolchitosan as a multivalent linker. The established system appeared to describe well the interactions of heparin with such proteins as acidic and basic fibroblast growth factors and tissue factor pathway inhibitor.

Biosensing Techniques↗

PubMed2001

A molecular mimic of phosphorylated prolactin markedly reduced tumor incidence and size when DU145 human prostate cancer cells were grown in nude mice.

Others have demonstrated the presence of an autocrine prolactin (PRL) growth loop in the normal human prostate. In this study we have used three human prostate cancer cell lines but have focused on the androgen-independent human prostate cancer cell line, DU145, to ask: (a) whether this autocrine growth loop is maintained beyond the loss of androgen sensitivity in the progression of prostate cancer; and (b) whether interruption of this growth loop by a PRL receptor antagonist, an S179D mutant PRL, could inhibit the formation of DU145-derived tumors. The autocrine loop was examined in most detail in the DU145 cell line but was demonstrated to be functional in all three of the lines by the reversible inhibition of growth in vitro by the S179D PRL receptor antagonist. To investigate the effect of S179D PRL on the growth of DU145 tumors in nude mice two sets of experiments were performed. In the first set, Alzet minipumps containing no PRL, wild-type (WT) PRL, or the S179D PRL (the last two delivering 4.56 microg/24 h and 4.26 microg/24 h, respectively), were implanted s.c. on day 1. On day 4, 5 x 10(6) DU145 cells were injected s.c. in the hindquarter. On day 22, the animals were killed, tumors were removed, measured, and subsequently fixed and processed for histological confirmation of tumor formation. The incidence of tumors in the no-PRL control group was 9/11 animals (82%). In the animals treated with WT PRL, the incidence was 8/10 (80%), whereas in the animals treated with the S179D PRL, the incidence was markedly reduced to 3/11 (27%). Although WT PRL had no effect on the incidence of tumors, the average size of the tumors increased from 25.8 +/- 5.99 mm(3) in controls to 66.66 +/- 18.06 mm(3) in WT PRL-treated animals. In the second set of experiments, 5 x 10(6) DU145 cells were injected on day 1. On day 18, Alzet minipumps containing no PRL, WT PRL, or S179D PRL were implanted. On day 42, the animals were killed and the tumors processed as before. S179D PRL caused a reduction in tumor size from 1731 +/- 283 mm(3) in the no-PRL controls to 1031 +/- 295 mm(3), whereas WT PRL slightly increased the size to 2118 +/- 630 mm(3). We conclude that PRL is used as an autocrine growth factor by human prostate cancer cells both in vitro and in vivo and that interruption of this growth loop in vivo inhibits tumor initiation and the growth of well-established tumors.

Androgens↗

PubMed2001

A critical role for interleukin 18 in primary and memory effector responses to Listeria monocytogenes that extends beyond its effects on Interferon gamma production.

The stimulation of interferon (IFN)-gamma by interleukin (IL)-12 has been shown to provide protection from intracellular pathogens such as Listeria monocytogenes. Tumor necrosis factor (TNF) is also a major player in the resolution of Listeria infections and is suggested to have more global effects than can be explained by the induction of IFN-gamma alone. Since IL-18 synergizes with IL-12 to induce IFN-gamma production by natural killer and T helper (Th)1 cells, we determined its role in responses to Listeria. IL-18 appeared to be even more potent than either IL-12 or IFN-gamma for protection against this pathogen and IL-18 enhanced bacterial clearance in the complete absence of IFN-gamma. Indeed IL-18 was comparable to TNF in its ability to resolve the infection and showed a lowered protective capacity in the absence of TNF. Moreover, IL-18 induced macrophages to secrete both TNF and nitric oxide after a Listeria infection. IL-18 was also essential for optimal IFN-gamma production by antigen-specific T cells. Therefore, IL-18 operates via its effects on both the innate immune response, including macrophages, as well as on Th1 cells, to protect against Listeria.

Animals↗

PubMed2001

Modulation of mouse neural crest cell motility by N-cadherin and connexin 43 gap junctions.

Connexin 43 (Cx43alpha1) gap junction has been shown to have an essential role in mediating functional coupling of neural crest cells and in modulating neural crest cell migration. Here, we showed that N-cadherin and wnt1 are required for efficient dye coupling but not for the expression of Cx43alpha1 gap junctions in neural crest cells. Cell motility was found to be altered in the N-cadherin-deficient neural crest cells, but the alterations were different from that elicited by Cx43alpha1 deficiency. In contrast, wnt1-deficient neural crest cells showed no discernible change in cell motility. These observations suggest that dye coupling may not be a good measure of gap junction communication relevant to motility. Alternatively, Cx43alpha1 may serve a novel function in motility. We observed that p120 catenin (p120ctn), an Armadillo protein known to modulate cell motility, is colocalized not only with N-cadherin but also with Cx43alpha1. Moreover, the subcellular distribution of p120ctn was altered with N-cadherin or Cx43alpha1 deficiency. Based on these findings, we propose a model in which Cx43alpha1 and N-cadherin may modulate neural crest cell motility by engaging in a dynamic cross-talk with the cell's locomotory apparatus through p120ctn signaling.

Animals↗

PubMed2001

Down-regulation of IL-12 p40 gene in Plasmodium berghei-infected mice.

We analyzed the mechanism that causes suppression of IL-12 p40 gene induction during Plasmodium berghei infection. Although IL-12 together with IFN-gamma plays an important role in protection against pathogenic infection, the IL-12 p70 protein production of infected macrophages is lower than that by the uninfected macrophages. We showed in the present study that the induction of IL-12 p40 gene but not IL-12 p35 gene in macrophages of P. berghei-infected mice was profoundly inhibited. The inhibition was induced by interaction with macrophages that had contacted with P. berghei-infected erythrocytes and was mediated by a soluble factor, IL-10. There was comparable activation of NF-kappaB in uninfected and infected cells. The induction of IFN-regulatory factor-1 gene was comparable in transcription level in uninfected and infected cells, while the unidentified complex formation of IFN-regulatory factor-1 was observed in infected cells. Therefore, the inhibition of the IL-12 p40 gene induction appeared to be regulated at transcriptional regulation level of the gene.

Animals↗

PubMed2001

Hyaluronan synthase 3 overexpression promotes the growth of TSU prostate cancer cells.

Hyaluronan synthase 3 (HAS3) is responsible for the production of both secreted and cell-associated forms of hyaluronan and is the most active of the three isoforms of this enzyme in adults. In this study, the cDNA for human HAS3 was cloned and characterized. The open reading frame consisted of 1659 bp coding for 553 amino acids with a deduced molecular weight of about 63,000 and isoelectric pH of 8.70. The sequence of human HAS3 displayed a 53% identity to HAS1 and a 67% identity to HAS2. It also contained a signal peptide and six potential transmembrane domains, suggesting that it was associated with the plasma membrane. To evaluate the physiological role of human HAS3, expression vectors for this protein were transfected into TSU cells (a prostate cancer cell line), and the phenotypic changes in these cells were examined. The enhanced expression of hyaluronan in the transfected cells was demonstrated by dot blot analysis and ELISA. These cells were found to differ from their vector-transfected counterparts with respect to the following: (a) they grew at a faster rate in high (but not low) density cultures; (b) conditioned media from these cells stimulated the proliferation and migration of endothelial cells; (c) when placed on the chorioallantoic membrane of chicken embryos, these cells formed large, dispersed xenografts, whereas the control transfectants formed compact masses; and (d) when injected s.c. into nude mice, the xenografts formed by HAS3 transfectants were bigger than those formed by control transfectants. Histological examination of these xenografts revealed the presence of extracellular hyaluronan that could act as conduits for the diffusion of nutrients. In addition, they had a greater number of blood vessels. However, the HAS3-transfected TSU cells did not display increased metastatic properties as judged by their ability to form lung masses after i.v. injection. These results suggested that the HAS3-induced overexpression of hyaluronan enhanced tumor cell growth, extracellular matrix deposition, and angiogenesis but was not sufficient to induce metastatic behavior in TSU cells.

Allantois↗

PubMed2001

Effect of the structure of natural sterols and sphingolipids on the formation of ordered sphingolipid/sterol domains (rafts). Comparison of cholesterol to plant, fungal, and disease-associated sterols and comparison of sphingomyelin, cerebrosides, and ceramide.

Ordered lipid domains enriched in sphingolipids and cholesterol (lipid rafts) have been implicated in numerous functions in biological membranes. We recently found that lipid domain/raft formation is dependent on the sterol component having a structure that allows tight packing with lipids having saturated acyl chains (Xu, X., and London, E. (2000) Biochemistry 39, 844-849). In this study, the domain-promoting activities of various natural sterols were compared with that of cholesterol using both fluorescence quenching and detergent insolubility methods. Using model membranes, it was shown that, like cholesterol, both plant and fungal sterols promote the formation of tightly packed, ordered lipid domains by lipids with saturated acyl chains. Surprisingly ergosterol, a fungal sterol, and 7-dehydrocholesterol, a sterol present in elevated levels in Smith-Lemli-Opitz syndrome, were both significantly more strongly domain-promoting than cholesterol. Domain formation was also affected by the structure of the sphingolipid (or that of an equivalent "saturated" phospholipid) component. Sterols had pronounced effects on domain formation by sphingomyelin and dipalmitoylphosphatidylcholine but only a weak influence on the ability of cerebrosides to form domains. Strikingly it was found that a small amount of ceramide (3 mol %) significantly stabilized domain/raft formation. The molecular basis for, and the implications of, the effects of different sterols and sphingolipids (especially ceramide) on the behavior and biological function of rafts are discussed.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed2001

Support vector machines for predicting protein structural class.

BACKGROUND: We apply a new machine learning method, the so-called Support Vector Machine method, to predict the protein structural class. Support Vector Machine method is performed based on the database derived from SCOP, in which protein domains are classified based on known structures and the evolutionary relationships and the principles that govern their 3-D structure. RESULTS: High rates of both self-consistency and jackknife tests are obtained. The good results indicate that the structural class of a protein is considerably correlated with its amino acid composition. CONCLUSIONS: It is expected that the Support Vector Machine method and the elegant component-coupled method, also named as the covariant discrimination algorithm, if complemented with each other, can provide a powerful computational tool for predicting the structural classes of proteins.

Algorithms↗

PubMed2001

Uroplakin as a marker for typing metastatic transitional cell carcinoma on fine-needle aspiration specimens.

BACKGROUND: Immunohistological markers specific for a single type of epithelium are rare. Recently, urothelium tissue-specific genes were cloned. The genes encoded a family of transmembrane proteins, uroplakins, that are expressed only in urothelial mucosa. Using uroplakin antibodies on paraffin-embedded tissue, a previous study demonstrated positive staining in 66% of metastatic transitional cell carcinoma (TCC) cases and negative staining in all other tumors (including breast, ovarian, lung, and gastrointestinal carcinomas) tested. The current study addresses the diagnostic value of uroplakins in conventional fine-needle aspiration (FNA) material in establishing a diagnosis of metastatic TCC. METHODS: Representative slides from 27 FNA cases of metastatic TCC and 52 non-TCC carcinomas were collected. The avidin-biotin-peroxidase method was utilized, using polyclonal antiuroplakin as the primary antibody on 95% ethanol-fixed, Papanicoloau-stained direct smears. RESULTS: Twenty-five of 27 metastatic TCC cases (93%) were found to stain positively for uroplakin with a superficial membrane/microluminal staining pattern. A few cells with diffuse membranous staining also were noted in 48% of the positive metastatic TCC cases. The superficial membrane/microluminal staining pattern was not observed in any of the non-TCC carcinomas. However, approximately 6% of these cases (3 of 52 cases) did show rare tumor cells with diffuse membranous staining. CONCLUSIONS: The application of uroplakin antibodies to 95% ethanol-fixed FNA direct smears has improved the sensitivity of the antibody for metastatic TCC while maintaining a specificity comparable to that of paraffin-embedded tissue. The authors believe that these antibodies have diagnostic potential in cytopathology in the evaluation of metastatic TCC.

Adult↗

PubMed2001

Tofu consumption and blood lead levels in young Chinese adults.

Tofu is a commonly consumed food in China. Tofu may interfere with lead absorption and retention because of its high calcium content. In this observational study, the authors examined whether dietary tofu intake was associated with blood lead levels among young adults in Shenyang, China. The analyses included 605 men and 550 women who completed baseline questionnaires and had blood lead measurements taken in 1996-1998 as part of a prospective cohort study on reproductive health. Mean blood lead levels were 13.2 microg/dl in men and 10.1 microg/dl in women. Blood lead levels were negatively associated with tofu intake in both genders. A linear trend test showed a 3.7% (0.5-microg/dl) decrease in blood lead level with each higher category of tofu intake (p = 0.003). The highest tofu intake group (> or =750 g/week) had blood lead levels 11.3% lower (95% confidence interval: 4.1, 18.0) than those of the lowest tofu intake group (<250 g/week). In all regression models, data were adjusted for gender, age, height, body mass index, district, cigarette smoking, alcohol drinking, education, occupation, use of vitamin supplements, season, and dietary intake of meat, fish, vegetables, eggs, and milk. In conclusion, the authors found a significant inverse dose-response relation between tofu consumption and blood lead levels in this Chinese population.

Adult↗

PubMed2001

Nonsteroidal anti-inflammatory drugs induce apoptosis in esophageal cancer cells by restoring 15-lipoxygenase-1 expression.

In previous studies, we have found that expression of 15-lipoxygenase-1 (15-LOX-1) and its main product, 13-S-hydroxyoctadecadienoic acid, are decreased in human colorectal cancers and that nonsteroidal anti-inflammatory drugs (NSAIDs) can therapeutically induce 15-LOX-1 expression to trigger apoptosis in human colorectal cancer cells. NSAIDs similarly induce apoptosis in esophageal cancer cells, although the mechanisms of these effects remain to be defined. In the present study, we tested whether 15-LOX-1 is down-regulated in human esophageal cancers using paired normal and tumor human surgical samples and whether NSAIDs can up-regulate 15-LOX-1 to restore apoptosis in esophageal cancer cells. We found that: (a) 15-LOX-1 was down-regulated in human esophageal carcinomas; (b) NSAIDs induced 15-LOX-1 expression during apoptosis in esophageal cancer cells; and (c) 15-LOX-1 inhibition suppressed NSAID-induced apoptosis, which was restored by 13-S-hydroxyoctadecadienoic acid but not by its parent compound, linoleic acid. These findings demonstrate that 15-LOX-1 is down-regulated in human esophageal carcinomas and that NSAIDs induce apoptosis in esophageal cancer cells via up-regulation of 15-LOX-1. They also support the concept that the loss of the proapoptotic role of 15-LOX-1 in epithelial cancers is not limited to human colorectal cancers.

Adenocarcinoma↗