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PubMed2004

Overexpression of estrogen receptor-alpha gene suppresses gap junctional intercellular communication in endometrial carcinoma cells.

Stimulation of the endometrium by estrogens without the differentiating effect of progestins is the primary etiological factor associated with the development of endometrial hyperplasia and adenocarcinoma. However, the correlation between sex steroids and gap junctional intercellular communication (GJIC), which is considered to play an important role in the control of cell growth and differentiation, is not well known in endometrial carcinoma. In this study, we focused on the influence of estrogen and its receptor in connexin (Cx) expression and GJIC in endometrial carcinoma cells, established stable clone IK-ER1 overexpressing ER-alpha to transfect the expression vector and analysed them in various hormonal conditions. The growth of IK-ER1 was accelerated by 17beta-estradiol and the acceleration of the 5-bromo-25-deoxyuridine labeling index was observed. GJIC was assayed by scoring the number of dye-coupled cells after microinjection of single cells with Lucifer-Yellow, and subcellular localization of Cx26 and Cx32 was analysed by immunocytochemistry. In the presence of estradiol, dye-coupled cells of IK-ER1 were significantly reduced compared to those without estradiol and the reduction was completely inhibited by adding ICI182.780, a pure antiestrogen substrate. Cxs were detected as only small spots by immunocytochemistry, and Western blotting showed that the expression was decreased. These results suggest that activation of ER-alpha by estrogen results in tumor progression by stimulating cell growth and suppressing GJIC via suppression of the expression of Cxs in endometrial carcinogenesis.

Cell Communication↗
PubMed1995

Malignantly transformed non-parenchymal liver epithelial cells and transformed oval cells suppress the homotypical gap junctional intercellular communication of co-cultured rat liver parenchymal cells.

Isolated rat liver parenchymal cells (PC) were co-cultured with a non-parenchymal rat liver epithelial cell line (NEC) or with an oval cell line. The homotypical gap junctional intercellular communication (GJIC) between the liver PC was measured after microinjection of Lucifer Yellow by dye transfer. The rat liver PC were dye coupled between 87% and 100% for at least 1 week in both co-cultures, in contrast to PC In monoculture between which no dye coupling was left after 1 week. When liver PC were co-cultured with a transformed and tumorigenic NEC or with a transformed and tumorigenic oval cell line the homotypical GJIC between the liver PC was drastically decreased with culture time, and the PC were then compressed and displaced by the expansive growth of the transformed cell lines. The disturbance of the GJIC between normal cells by adjacent tumorigenic cells might be a new mechanism to explain the expansive growth of tumors.

Animals↗
PubMed1997

Comparative effects of clofibrate and methyl clofenapate on morphological transformation and intercellular communication of Syrian hamster embryo cells.

The Syrian hamster embryo (SHE) cell system was used to evaluate the ability of two hepatocarcinogenic structurally related peroxisome proliferators (PPs) to induce morphological transformation (MT) of SHE colonies and to inhibit gap junctional intercellular communication (GJIC). Clofibrate and methyl clofenapate (MCP), which was shown to be a more active PP and a more potent carcinogen in vivo than clofibrate, were compared. MCP appeared slightly more active in vitro than clofibrate in affecting MT and GJIC of SHE cells. The morphological transformation of SHE colonies was induced by 50 microM MCP, against 100 microM clofibrate. Moreover, 50 microM MCP potentiated the transforming effects of both benzo[a]pyrene and 12-O-tetradecanoylphorbol-13-acetate. The inhibition of GJIC, measured by transfer of lucifer yellow, was transient and occurred at concentrations inducing morphological transformation. MCP inhibited dye transfer at 50 microM and the inhibition lasted up to 24 h at 100 microM. Inhibition of communication lasted only 4 h with clofibrate and occurred at a higher concentration (175 microM). This study showed that both the SHE cell transformation and dye transfer assays were able to display the different activities of the two PPs, even though the difference in potency observed was smaller than in vivo. It also revealed interactions between non-genotoxic carcinogens and the ability of the SHE cell transformation assay to detect these combined effects.

Animals↗
PubMed1994

[Studies on the reduction of malignant phenotypes in a highly metastatic human lung carcinoma--correlated changes of intercellular communication, cytoskeletons, oncogenes and antioncogene].

Human lung giant cell carcinoma cell line PG is characterized by its highly metastatic (100%) behavior in nude mice. When compared with cultured normal human fetal lung cells, PG cells were deficient in gap junctional intercellular communication (GJIC) function as detected by Scrape Loading and Dye Transfer method. Tubulin immunofluorescent and rhodamine-phalloidin staining revealed disorganization of microtubules and disruption of stress fibers with appearance of reorganized F-actin-bodies in PG cells. Northern or dot blot hybridization results showed that PG expressed high levels of c-myc and c-Ha-ras oncogenes and low level of antioncogene P53. Southern hybridization demonstrated that PG also exhibited c-myc gene amplification. When PG was treated with calmodulin antagonist calmidazolium (CDZ, 100-200nmol/L) or a Chinese medicinal mixture L2 (3-13mg/ml), cell proliferation was inhibited, GJIC function restored, and microtubule network recovered. But only L2 was efficient in (1) improving the stress fiber organization, (2) inhibiting the colony formation in soft agar, (3) reduction of c-myc amplification and expression, and (4) up-regulation of P53 mRNA level. The correlation between markers of malignant phenotypes and the reversion of PG cells is discussed.

Animals↗
PubMed1996

[Intercellular communication studied by using the gap junctions in a primary cell culture of human aortic intima].

The rate of gap junction communication has been investigated in the primary culture of highly differentiated mesenchymal cells (subendothelial smooth muscle cells isolated from grossly normal and atherosclerotic areas of human aorta), and in poorly differentiated cells of mesenchymal origin (adult human skin fibroblasts as well as skin fibroblasts and aortic smooth muscle cells derived from human fetus). In cell cultures isolated from grossly normal and atherosclerotic aorta the number of cells coupled via gap junction increased with cell density and reached the plateau at a cell density of 50-70 cells/mm2. In cultures of normal aortic cells the number of coupled cells was significantly higher than in cultures of atherosclerotic cells. Gap junctional communication between cells loaded with lipid inclusions was lower that that between cells free of excess of intracellular lipids. In cultures of human skin fibroblasts the rate of intercellular communication was comparable to that in cultures of atherosclerotic cells. There was practically no cell-to-cell communication in cultures of fetal cells. It is hypothesized that the reduced gap junctional communication in atherosclerotic human aorta is associated with alterations in the degree of smooth muscle cell differentiation.

Adult↗
PubMed1991

Molecular mechanisms of TPA-mediated inhibition of gap-junctional intercellular communication: evidence for action on the assembly or function but not the expression of connexin 43 in rat liver epithelial cells.

We found that a rat liver epithelial cell line (IAR 20) expresses connexin 43, the major cardiac gap-junction protein, but not connexin 26 or connexin 32, major liver gap-junction proteins. The effects of TPA on connexin 43 expression in IAR 20 were investigated using northern blot analysis, western blot analysis, and an immunofluorescence technique. Gap-junctional intercellular communication (GJIC) in this cell line decreased within 60 min of 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment and recovered after 24 h. The number of immunofluorescence spots of connexin 43 on IAR 20 was closely related to the change in GJIC induced by TPA. However, TPA did not change the level of mRNA measured by northern blot analysis. Moreover, connexin 43 protein expression analyzed by western blotting suggests that connexin 43 proteins were still present in TPA-treated cells at a similar level. These results suggest that GJIC of these rat liver epithelial cells was mediated by connexin 43 protein and that TPA inhibited GJIC by inhibiting posttranslational processing of connexin 43 proteins, e.g., localization or assembly.

Animals↗
PubMed1989

Intercellular communication between rat anterior pituitary cells.

Cell-to-cell communication within the rat anterior pituitary was investigated in 60-day-old male rats with immunohistochemistry, scanning electron microscopy, freeze-fracture electron microscopy, and conventional transmission electron microscopy. A dense cytoreticular network of cytoplasmic processes from the folliculostellate cells was found to contain immunoreactive S-100 protein and was observed throughout the anterior pituitary. Nonimmunoreactive cells, which were granular, were situated in the center of each network. Almost all of the granulated cells were situated in close proximity to the folliculostellate cells. Scanning electron microscopy revealed that the gland consisted of microlobules enclosed by a basal lamina. On the surface of the microlobules were blood vessels whose branches invaded its internal structures. Cytoplasmic processes from folliculostellate cells projected outside the microlobule. Freeze-fracture electron microscopy demonstrated the presence of numerous intramembranous particles on the P-face of the plasma membrane. Scattered on the cell surface were groups of particles forming gap junctions. Meshworks of ridges which were representations of tight junctions were also observed near clusters of microvillous fragments. Clusters of particles forming small gap junctions were located between the meshworks of tight junctions. Small gap junctions were clearly observed by conventional electron microscopy between junctional complexes in a manner similar to that seen by freeze-fracture electron microscopy. Slender cytoplasmic processes of folliculostellate cells came in contact near the basal lamina and were adjoined by small gap junctions. The ratio of nongranular cells which contained gap junctions to those in which the junctions were absent was about 1:1. The size of the gap junctions ranged from 50 nm to 3 microns. No gap junctions were observed along the plasma membranes of the granular cells. The significance of an intercellular communication system within the anterior pituitary gland of the rat is to establish a mechanism for rapid transmission of information in an organ which lacks direct innervation.

Animals↗
PubMed1984

An in vitro model for studies of intercellular communication in cultured rat anterior pituitary cells.

The formation of intimate associations among different hormone-secreting cells within the rat adenohypophysis may serve as a possible site for physiologic regulation. In this report we describe a high density plating method which enables us to study cell-to-cell interactions within anterior pituitary cell cultures. Trypsin-dispersed pituitary cell suspensions attach rapidly (within 6 hr) and quantitatively (95-97%) to glass or plastic surfaces when plated in medium containing microM calcium concentrations (pH 7.6-7.8). Freshly plated cell suspensions obtained from female pituitary glands contained subpopulations of mammotrophs 49.3%, somatotrophs 30.3%, gonadotrophs 12.6%, corticotrophs 3.4% and thyrotrophs 1.5%. Epithelial cell colonies were formed during a 3-day culture period as the cells flattened and re-established contacts with neighboring cells. Freeze-fracture electron microscopic analysis of these colonies produced morphological evidence for direct intercellular contacts among the hormone-secreting cells. Large areas of tight junctions and small gap junctions were identified on the membranes of the epithelial cells within these colonies. Cells which contained tight junctions usually contained microvilli and morphological signs of active hormone secretion. Small junctional plaques containing tightly packed intramembrane particles were also occasionally found on the membranes of cells which were actively secreting pituitary hormones. The high density plating procedure which is described in this report provides greater opportunity for cell-cell interaction and thus may prove to be a useful model for evaluating the role of intercellular communication within this tissue.

Animals↗
PubMed1994

Interleukin-1 alpha suppresses gap junction-mediated intercellular communication in human endothelial cells.

Interleukin-1 alpha (IL-1 alpha) is a potent modulator of endothelial cell-surface properties and function as well as an inhibitor of endothelial cell proliferation. The present experiments demonstrate that IL-1 alpha can also suppress gap junction activity as measured by dye-coupling assays on human umbilical vein endothelial cells (HUVEC). The effect of IL-1 alpha is dose- and time-dependent, inhibitable by IL-1 receptor antagonist, independent of changes in intracellular [Ca+2], and distinguishable from the short-term effects of phorbol 12-myristate 13-acetate. Interestingly, IL-1 alpha was not effective in reducing cell communication in senescent HUVEC which exhibit lower coupling than early-passage cells and for which elevated levels of IL-1 alpha transcript and polypeptide had been reported previously. These results suggest a novel role for IL-1 alpha in the regulation of intercellular communication, which may be related to its role as a regulator of endothelial differentiation and senescence.

Alkaloids↗
PubMed2002

Increase in gap junctional intercellular communication by high molecular weight hyaluronic acid associated with fibroblast growth factor 2 and keratinocyte growth factor production in normal human dermal fibroblasts.

The effects of different molecular weights of hyaluronic acid (HA), a major component of extracellular matrix, on gap junctional intercellular communication (GJIC) in normal human dermal fibroblasts (NHDF cells) were investigated. NHDF cells were cultured for 4 days with different molecular weights of HA and then the extent of GJIC was assessed by the scrape-loading dye transfer method, using Lucifer yellow. The area of dye transfer was greater in the dishes coated with HA than in those to which HA was added. Thus, NHDF cells cultured on surfaces coated with high molecular weight (HMW) HA (MW, 800 kDa) showed greatly enhanced GJIC. Furthermore, another aim of this study was to evaluate the effects of different molecular weights of HA on the production of FGF-2 and KGF, because both are important cytokines produced by NHDF cells. When FGF-2 and KGF cultured levels of cell extracts and media were determined by ELISA, both levels were significantly enhanced when cells were grown on plates coated with HMW HA. This finding indicated that the function of gap junction channels in NHDF cells grown on plates coated with HMW HA may promote the biosynthesis of growth factors such as FGF-2 and KGF.

Cell Communication↗
PubMed1995

Irsogladine activates gap-junctional intercellular communication through M1 muscarinic acetylcholine receptor.

Irsogladine, an agent that protects gastric mucosa against various ulcerogenic stimuli through increasing cyclic AMP in surface mucous cells, has been reported to dose-dependently (10(-7) to 10(-5) M) facilitate gap-junctional intercellular communication (GJIC) in gastric epithelial cells. The beta adrenergic agonist, isoproterenol, stimulates GJIC in resting cells and inhibits GJIC in cells activated by 3-isobutyl-1-methylxanthine. In this study, we investigated whether irsogladine acts on GJIC in a manner similar to that shown by isoproterenol. Irsogladine, which bound to M1 muscarinic acetylcholine receptors (mAChR), did not inhibit, but failed to further facilitate the 3-isobutyl-1-methylxanthine-enhanced GJIC, measured by Lucifer yellow transfer. The enhancement of GJIC by irsogladine was inhibited by the M1 mAChR antagonist, pirenzepine. A selective M1 mAChR agonist, McN-A-343, enhanced GJIC. Isoproterenol (10(-8) to 10(-6) M), which alone did not affect GJIC, inhibited the GJIC enhanced by 10(-5) M irsogladine. Conversely, 10(-10) to 10(-6) M irsogladine, which alone did not affect GJIC, inhibited the GJIC enhanced by 10(-5) M isoproterenol. McN-A-343 also converted the action of 10(-5) M isoproterenol from facilitation to inhibition of GJIC. These results indicate that GJIC is heterologously down-regulated by cross-talk between M1 mAChR and beta adrenergic receptors. In addition, the effects of irsogladine and isoproterenol at low concentrations suggest the involvement of another mechanism for down-regulating GJIC.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1996

Lack of tumor-promoting effects of flavonoids: studies on rat liver preneoplastic foci and on in vivo and in vitro gap junctional intercellular communication.

Possible tumor-promoting activity of four flavonoids, quercetin (QC), tangeretin (TG), flavone (FO), and flavanone (FN), was examined in a rat liver short-term carcinogenesis assay as well as with in vivo and in vitro assays of inhibition of gap junctional intercellular communication (GJIC). Rat hepatocarcinogenesis was induced by aflatoxin B1 treatment followed by a selection phase (2-acetylaminofluorene treatment and partial hepatectomy), then treatment with or without test chemicals (in vivo studies of antipromotion were not performed). Using glutathione S-transferase placental form (GST-P)-positive foci, we compared the effects of flavonoids (at 1,000 ppm in the diet) with the effects of phenobarbital (PB) on the occurrence of liver preneoplastic lesions. In addition, we studied the effects of flavonoids on GJIC in the livers derived from these experiments and in two types of cultured cells. No significant difference in the number and area of GST-P-positive foci was found after one or three months of treatment between any flavonoid group and control group. In the positive control group, PB markedly increased the numbers and areas of preneoplastic lesions at three months. Whereas PB also decreased by 60% the average size of lucifer yellow dye spread in slices of liver parenchyma free of preneoplastic lesions among the different flavonoids, only TG decreased the dye transfer in vivo: by 30% at one month and 50% at three months. With the dye transfer assay applied to a rat liver epithelial cell line (REL) and the Chinese hamster V79 metabolic cooperation assay, none of the tested flavonoids (< or = 25 microM) inhibited GJIC. Conversely, protective properties were seen for some of the compounds in antipromotion in vitro studies, because TG and FN enhanced the dye transfer in REL cells and FO, TG, and QC partly prevented the inhibition of metabolic cooperation by 12-O-tetradecanoylphorbol-13-acetate. Thus, taken together, our results suggest that QC, FO, and FN do not show tumor-promoting activity. Concerning TG, some discrepancies in the in vivo data are observed. Some of them (GJIC inhibition in liver slices) are probably more relevant to promotion of hepatocarcinogenesis.

2-Acetylaminofluorene↗
PubMed1990

Effects on intercellular communication in human keratinocytes and liver-derived cells of polychlorinated biphenyl congeners with differing in vivo promotion activities.

Several purified polychlorinated biphenyl (PCB) congeners with differing toxicity/tumor promotional activities in rat liver in vivo were tested for their effects on gap-junctional intercellular communication (GJIC) in cell strains and lines derived from human liver and skin. This in vitro assay is being developed to detect various classes of tumor promoters. The 3-methylcholanthrene (MCA)-type cytochrome P450 inducer and hepatotoxic promoter 3,3',4,4'-tetrachlorobiphenyl was inactive in this assay for all of the cells tested, suggesting this promoter acts by other mechanisms. The phenobarbital-like enzyme inducer and less toxic promoter 2,2',4,4',5,5'-hexachlorobiphenyl inhibited GJIC in both liver and skin cells, whereas the 2,2',5,5'-tetrachlorobiphenyl congener, which does not act as a promoter in rat liver, inhibited GJIC only in the skin cell types and in one of the liver cell strains thought to be of bile duct origin. 2,3,4,4',5-Pentachlorobiphenyl, a mixed (phenobarbital plus MCA) inducer of cytochrome P450, inhibited GJIC in both liver and skin cells, suggesting that it may be a promoter in vivo. The results suggest that GJIC inhibition is a property of PCB congeners with phenobarbital-like enzyme induction capabilities, and that there exist some tissue/cell type differences in sensitivity to these congeners.

Carcinogens↗
PubMed1997

Effects of peroxisome proliferators and 12-O-tetradecanoyl phorbol-13-acetate on intercellular communication and connexin43 in two hamster fibroblast systems.

Effects of 12-O-tetradecanoyl phorbol 13-acetate (TPA) and the hepatic peroxisome proliferators (HPPs) clofibrate, methyl clofenapate (MCP), di(2-ethylhexyl)phthalate (DEHP) and mono(2-ethylhexyl)phthalate (MEHP) were studied in 2 gap junctional intercellular communication (GJIC) systems, metabolic cooperation in V79 cells and microinjection/dye transfer in Syrian hamster embryo (SHE) cells and V79 cells. TPA inhibited GJIC in both systems but was considerably more potent in V79 cells. SHE cells showed a rapid and transient inhibition of GJIC after exposure to HPPs, with maximal inhibition occurring at 5-15 min. The transient inhibition could be caused by metabolization of the compounds. Clofibrate and MEHP produced strong inhibition of metabolic cooperation in V79 cells at high concentrations, while the effect of MCP and DEHP was lower. However, DEHP, MEHP and clofibrate strongly inhibited dye transfer in V79 cells after a 30 min exposure. Clofibrate also showed a dose- and time-dependent effect on dye transfer in V79 cells. The phosphorylation status of the gap junction protein connexin43 (Cx43) changed minimally in SHE cells after exposure to TPA or HPPs. Cx43 from V79 cells was strongly affected by TPA, but not by HPPs. Immunofluorescence of Cx43 disappeared in both cell types when they were exposed to TPA and MEHP, but not to the other HPPs. Thus, there is no direct correlation between the inhibition of GJIC and changes in the phosphorylation status of Cx43 or the appearance of Cx43 in immunofluorescence experiments. The discrepancies may partly be explained by binding of accessory proteins to Cx43. We point out sequences that may be involved in such binding.

Animals↗
PubMed1995

Inhibition of gap junctional intercellular communication and malignant transformation of rat liver epithelial cells by neu oncogene.

A retrovirus containing a neu oncogene was introduced into a Fischer F344 rat liver epithelial cell line (WB-F344) to study the effect of the expression of neu oncoprotein on gap junctional intercellular communication (GJIC), the ability to form colonies in soft agar and the ability to form tumors in rat liver by these cells. After viral infection, five different neu-transduced epithelial clones were randomly selected for further analysis. Southern blot analysis of HindIII-digested genomic DNA hybridized with a neu-specific probe indicated that the neu oncogene carried by the retrovirus was integrated into different chromosomal locations in the five different neu-transduced WB cell lines. Using the fluorescence recovery after photobleaching (FRAP) assay, we found that GJIC was significantly reduced in neu-transduced WB clones, compared with control virus-infected and parental WB cells. Western blot analysis of connexin 43 in the neu-transduced cell lines showed altered phosphorylation patterns compared with the normal WB-rat liver cell line. Confocal image analysis of the neu-transduced cells showed that the connexin 43 protein, as detected by fluorescent immunostaining, was localized in the cell nucleus. The neu-transduced WB cell lines also acquired the ability to grow in soft agar. Furthermore, cells from three of the five neu-transduced cell lines, when injected into the liver of Fischer F344 rats through the portal vein, were highly tumorigenic (multiple focal hepatic tumors developed within 2 weeks). Cells derived from the tumor were shown to be G-418 resistant, demonstrating that the tumor was derived from the injected WB-neu cells. The results of this study demonstrate that the expression of the neu oncogene is able to block GJIC and to induce tumorigenicity in the rat liver WB-F344 cell line.

Animals↗
PubMed2003

Inhibition of gap junctional intercellular communication by noncoplanar polychlorinated biphenyls: inhibitory potencies and screening for potential mode(s) of action.

Polychlorinated biphenyls (PCBs), a structurally diverse group of environmental pollutants, are effective promoters in two-stage cancer models, which implies that epigenetic mechanisms are involved. Inhibition of gap junctional intercellular communication (GJIC) belongs among critical epigenetic events of tumor promotion. We determined the relative potencies of a series of environmentally relevant PCB congeners to inhibit GJIC in vitro in a rat liver epithelial cell line with pluripotent oval cell characteristics. The nonplanar PCBs were potent inhibitors of GJIC, whereas the coplanar PCBs did not inhibit GJIC. We then compared the effects of the coplanar PCB 126 (3,3',4,4',5-pentachlorobiphenyl) and the noncoplanar PCB 153 (2,2',4,4',5,5'-hexachlorobiphenyl) with effects of two model GJIC inhibitors, a tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and epidermal growth factor (EGF). In contrast to TPA or EGF, PCB 153 elicited a long-term downregulation of GJIC (up to 48 h). Using Western blot analysis with phospho-specific antibodies, it was found that PCB 153, and not PCB 126, activated mitogen-activated protein kinases ERK1/2; however in contrast to TPA and EGF, this activation was observed at the time points subsequent to GJIC inhibition. Moreover, blocking of ERK1/2 activation did not prevent the GJIC inhibition induced by PCB 153. Therefore, additional intracellular signaling pathways potentially involved in the downregulation of GJIC by PCBs were screened by using specific chemical probes inhibiting serine/threonine kinases, tyrosine kinases, and phospholipases. The inhibition of diacylglycerol lipase partially blocked and the selective inhibition of Src kinases and phosphatidylcholine-specific phospholipase C (PC-PLC) completely blocked the inhibitory effects of the noncoplanar PCB on GJIC, indicating that PC-PLC or sphingomyelinase and Src might be upstream regulators of noncoplanar PCB-induced inhibition of GJIC.

Animals↗
PubMed2004

Inhibition of cyclooxygenase-2 expression and restoration of gap junction intercellular communication in H-ras-transformed rat liver epithelial cells by caffeic acid phenethyl ester.

One of the most frequent defects in human cancers is the uncontrolled activation of the ras signaling pathways. Increased expression of cyclooxygenase-2 (COX-2) and inhibition of gap junction intercellular communication (GJIC) have been frequently observed in several forms of human malignancies. The present study investigated the effects of caffeic acid phenethyl ester (CAPE), a chemopreventive phytochemical derived from honey propolis, on COX-2 expression and GJIC in Harvey-ras-transformed WB-F344 rat liver epithelial cells (H-ras WB cells). H-ras induced COX-2 expression in WB-F344 rat liver epithelial cells (WB cells). H-ras WB cells also exhibited complete inhibition of GJIC and predominant unphosphorylation of connexin 43 (Cx43), a major protein modulating GJIC. CAPE significantly inhibited the constitutive expression of COX-2 and restored the disrupted GJIC through the phosphorylation of Cx43 at a concentration of 12.5 microM in H-ras WB cells. Although the molecular basis for the cancer chemopreventive activity of CAPE is not completely understood, several studies suggest that CAPE is a potent and specific inhibitor of the transcription factor nuclear factor kappaB (NF-kappaB) activation. We also found that CAPE significantly inhibited H-ras-induced NF-kappaB DNA-binding activity without affecting the activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase, which are major intracellular molecules involved in the Ras signaling pathways. In conclusion, CAPE may exert cancer chemopreventive effects through the inhibition of COX-2 expression and the restoration of disrupted GJIC induced by H-ras, possibly by targeting NF-kappaB.

Animals↗
PubMed1994

Effect of 1,1'-(2,2,2-trichloroethylidene)-bis(4-chlorobenzene) (DDT) on gap junctional intercellular communication and morphological transformation of Syrian hamster embryo cells.

The organochlorine insecticide 1,1'-(2,2,2-trichloroethylidene)bis(4-chlorobenzene) (DDT) did not induce or promote induction of morphological transformation in Syrian hamster embryo (SHE) cells, but it was a potent inhibitor of gap junctional intercellular communication (GJIC). The kinase inhibitor staurosporine did not affect DDT induced inhibition of GJIC, although it has been shown to decrease the inhibitory effect of 12-O-tetradecanoyl-phorbol-13-acetate (TPA) on GJIC. In addition, pretreatment with TPA made the cells refractory to further TPA induced inhibition of GJIC, while they remained sensitive to DDT. Thus, DDT and TPA inhibit GJIC through different mechanisms. Elevation of cellular cyclic adenosine monophosphate (cAMP) level by exposure to forskolin counteracted the inhibitory effect of DDT similar to that observed for TPA. Continuous exposure to DDT at concentrations near the effective concentration (50%) value (EC50 value) resulted in a slight recovery of GJIC following the initial inhibition. This recovery was not accompanied by the cells becoming refractory to further DDT induced inhibition of GJIC. The recovery of GJIC after removal of the DDT containing medium seemed to be related to a reduction in the amount of cell-associated DDT.

Animals↗