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PubMed2000

Resveratrol reverses tumor-promoter-induced inhibition of gap-junctional intercellular communication.

The naturally occurring stilbene/alexin trans-resveratrol (trans-3,5, 4'-trihydroxystilbene) is a promising agent for the prevention of cancer. We investigated the effect of resveratrol on gap-junctional intercellular communication (GJIC) in WB-F344 rat liver epithelial cells because inhibition of GJIC is an important mechanism of tumor promotion. Seventeen to 50 microM resveratrol increased GJIC significantly by a factor of 1.3 compared with solvent vehicle controls, when the WB-F344 cells were exposed to resveratrol for 6 h. Most tumor promoters, including the phorbol ester TPA and the insecticide DDT, block GJIC. Resveratrol at 17-50 microM also significantly prevented down-regulation of GJIC by TPA and DDT, by a factor of 2.7 and 1.8, respectively. This recovery of GJIC from TPA inhibition was partly correlated with hindered hyperphosphorylation of Cx43. In conclusion, resveratrol was found to enhance GJIC and counteract the effects of tumor promoters on GJIC, and this is likely a mechanism that contributes to the antipromotional and anticarcinogenic properties of resveratrol.

Animals↗
PubMed1986

[Changes in the structure of the plasmalemma of hepatocytes and its specialized portions--intercellular junctions in man in complicated forms of cholelithiasis].

As demonstrates the electron microscopic investigation of the human liver at complicated forms of cholelithiasis, there is a stage-by-stage destruction of intercellular junctions and a change in the plasmolemma structure of hepatocytes depending on the degree of the disease. The greatest disorder in the plasmolemma structure is observed at gangrenous calculous cholecystitis, as well as at mechanical jaundice and suppurative cholangitis, dependent on choledocholithiasis. The most sensitive are the gap junctions; desmosomes and intermediate junctions are the second to suffer. The structure of the tight junctions is the last to be disturbed. This results in loss of specificity by different areas of plasmolemma in the hepatocytes, and the hepatocytes themselves loose their polarity. These alterations are evidently irriversible and result in death of the cells.

Cell Membrane↗
PubMed2005

Estrogenic compounds inhibit gap junctional intercellular communication in mouse Leydig TM3 cells.

Some estrogenic compounds are reported to cause testicular disorders in humans and/or experimental animals by direct action on Leydig cells. In carcinogenesis and normal development, gap junctional intercellular communication (GJIC) plays an essential role in maintaining homeostasis. In this study, we examine the effects of diethylstilbestrol (DES, a synthetic estrogen), 17beta-estradiol (E(2), a natural estrogen), and genistein (GEN, a phytoestrogen) on GJIC between mouse Leydig TM3 cells using Lucifer yellow microinjection. The three compounds tested produced GJIC inhibition in the TM3 cells after 24 h. Gradually, 10 microM DES began to inhibit GJIC for 24 h and this effect was observed until 72 h. On the other hand, both 20 microM E(2) and 25 microM GEN rapidly inhibited GJIC in 6 h and 2 h, respectively. The effects continued until 24 h, but weakened by 72 h. Furthermore, a combined effect at microM level between DES and E(2) on GJIC inhibition was observed, but not between GEN and E(2). DES and E(2) showed GJIC inhibition at low dose levels (nearly physiological estrogen levels) after 72 h, but GEN did not. DES-induced GJIC inhibition at 10 pM and 10 microM was completely counteracted by ICI 182,780 (ICl), an estrogen receptor antagonist. On the other hand, the inhibitory effects on GJIC with E(2) (10 pM and 20 microM) and GEN (25 microM) were partially blocked by ICI or calphostin C, a protein kinase C (PKC) inhibitor, and were completely blocked by the combination of ICI and calphostin C. These results demonstrate that DES inhibits GJIC between Leydig cells via the estrogen receptor (ER), and that E(2) and GEN inhibit GJIC via ER and PKC. These estrogenic compounds may have different individual non-genotoxic mechanism including PKC pathway on testicular carcinogenesis or development.

Animals↗
PubMedDate not supplied

Restoration of gap junctional intercellular communication by dibutyryl-cAMP in renal epithelial cells treated with renal carcinogen.

Dimethylnitrosamine(DMN) is an alkylating agent and a known renal carcinogen. A short exposure of renal epithelial cells to cytotoxic concentrations of DMN influences the expression of gap junction proteins. In this study, we examined gap junctional intercellular communication and connexin 43 expression in renal epithelial cells treated with 1% DMN and also examined the effects of dibutyryl-cAMP on preventing gap junctional disturbances. Connexin 43 becomes hypophosphorylated after treatment with 1% DMN for 15 minutes, but this hypophosphorylation is inhibited by pretreatment with dibutyryl-cAMP. These results suggest that changes in gap junction protein expression are early events associated with 1% DMN treatment of renal epithelial cells, and such changes are prevented by dibutyryl-cAMP pretreatment.

Animals↗
PubMed1988

Effects of sodium L-ascorbate, uracil, butylated hydroxyanisole and extracellular pH on junctional intercellular communication of BALB/c 3T3 cells.

To study the mechanism of tumor promotion by different classes of urinary bladder promoters, the effect of sodium L-ascorbate, uracil and butylated hydroxyanisole (BHA) on junctional intercellular communication was examined in cultured BALB/c 3T3 cells using a dye-transfer method. In addition, since administration of sodium L-ascorbate and several other bladder tumor promoters is known to result in increased urinary pH, the effect of pH of the culture medium on intercellular communication was investigated. Results showed that under the present experimental conditions on the BALB/c 3T3 cells, BHA inhibited intercellular communication while sodium L-ascorbate and uracil did not. Intercellular communication was inhibited in proportion to the increase of medium pH after incubation of 4 h. Although further study is necessary to confirm the negative results of sodium L-ascorbate and uracil, these results suggest differences in the promoting mechanism(s) among these agents.

Animals↗
PubMedDate not supplied

Effects of pyrethroid insecticides on gap junctional intercellular communications in Balb/c3T3 cells by dye-transfer assay.

The effects of fenvalerate, esfenvalerate, permethrin, cypermethrin, deltamethrin, p-chlorophenylisovaleric acid (CPIA, major metabolite of fenvalerate) and DDT, a liver tumor promoter, on gap junctional intercellular communication (GJIC) were examined in Balb/c3T3 cells by dye-transfer assay. Separate groups of Balb/c3T3 cells were exposed to the chemicals for 1 day. On the following day, GJIC was measured by counting the number of dye-transferring cells per injection of Lucifer Yellow under a fluorescent microscope. Fenvalerate, esfenvalerate, permethrin, cypermethrin, deltamethrin and DDT inhibited GJIC at noncytotoxic concentrations, while CPIA did not inhibit GJIC even at a cytotoxic concentration. It is concluded that the examined pyrethyroid insecticides, but not a metabolite, have inhibitory effects on GJIC in Balb/c3T3 cells.

3T3 Cells↗
PubMed2002

Increase in gap-junctional intercellular communications (GJIC) of normal human dermal fibroblasts (NHDF) on surfaces coated with high-molecular-weight hyaluronic acid (HMW HA).

Normal human dermal fibroblast (NHDF) cells were used to detect differences in gap-junctional intercellular communication (GJIC) by hyaluronic acid (HA), a linear polymer built from repeating disaccharide units that consist of N-acetyl-D-glucosamine (GlcNa) and D-glucuronic acid (GlcA) linked by a beta 1-4 glycosidic bond. The NHDF cells were cultured with different molecular weights (MW) of HA for 4 days. The rates of cell attachment in dishes coated with high-molecular-weight (HMW; 310 kDa or 800 kDa) HA at 2 mg/dish were significantly reduced at an early time point compared with low-molecular-weight (LMW; 4.8 kDa or 48 kDa) HA with the same coating amounts. HA-coated surfaces were observed by atomic force microscopy (AFM) under air and showed that HA molecules ran parallel in the dish coated with LMW HA and had an aggregated island structure in the dish coated with HMW HA surfaces. The cell functions of GJIC were assayed by a scrape-loading dye transfer (SLDT) method using a dye solution of Lucifer yellow. Promotion of the dye transfer was clearly obtained in the cell monolayer grown on the surface coated with HMW HA. These results suggest that HMW HA promotes the function of GJIC in NHDF cells. In contrast, when HMW HA was added to the monolayer of NHDF cells, the functions of GJIC clearly were lowered in comparison with the cells grown in the control dish or with those grown on the surface of HMW HA. Therefore it is concluded that the MW size of HA and its application method are important factors for generating biocompatible tissue-engineered products because of the manner in which the GJIC participates in cell differentiation and cell growth rate.

Cell Adhesion↗
PubMed2005

Expression of connexin 43 and gap junctional intercellular communication in the cumulus-oocyte complex in sheep.

To evaluate the effects of FSH, LH and/or cAMP on expression of connexin 43 (Cx43) in the ovine cumulus-oocyte complex (COC) and gap junctional intercellular communication (GJIC) of cumulus cells, two experiments were carried out. In experiment 1, Cx43 was immunodetected in the COC, before or after maturation, obtained from non-treated or FSH-treated ewes. The expression of Cx43 in the COC was greater (P < 0.01) on day 16 than on day 15 of the estrous cycle. In vivo FSH treatment decreased (P < 0.02) Cx43 expression on day 16 but not on day 15 of the estrous cycle. In experiment 2, intact COCs or isolated cumulus cells obtained from small and large follicles from FSH-treated ewes were cultured with or without FSH, LH or cAMP agonist and evaluated for GJIC by laser cytometry. For large follicles, the basal rate of GJIC was greater (P < 0.01) for cumulus cells in intact COCs than for isolated cumulus cells. FSH increased (P < 0.04) GJIC in cumulus cells in intact COCs and tended to increase (P < 0.1) GJIC in isolated cumulus cells from small follicles but decreased (P < 0.01) GJIC in cumulus cells in intact COCs from large follicles. LH also increased (P < 0.01) GJIC in isolated cumulus cells from small follicles but decreased GJIC in intact COCs (P < 0.01) and isolated cumulus cells (P < 0.02) from large follicles. cAMP increased (P < 0.01) the GJIC in both intact COCs and cumulus cells from small and large follicles. These results indicate that day of estrous cycle, stage of maturation and duration of FSH treatment affect expression of Cx43 in ovine COCs. In intact COCs, GJIC in cumulus cells was enhanced, probably due to the presence of the oocyte. In addition, the effects of FSH and LH, but not cAMP, on GJIC of cumulus cells depended on the stage of follicular development and on the presence of the oocyte.

Animals↗
PubMed1995

Inhibition of gap junctional intercellular communication between primary human smooth muscle cells by tumor necrosis factor alpha.

Tumor necrosis factor alpha (TNF alpha), a pleiotrophic cytokine present in atherosclerotic lesions, caused a dose-dependent and persistent reduction in gap junctional intercellular communication (GJIC) between primary human smooth muscle cells in vitro. A continuous presence of TNF alpha was required for this persistent inhibition. Pretreatment of smooth muscle cells with ascorbic acid, alpha-tocopherol or glutathione prevented this inhibition of GJIC by TNF alpha. The persistent blockage of GJIC by continuous exposure to TNF alpha suggests that TNF alpha may share some mechanistic similarities with exogenous tumor promoters. Furthermore, this reduction in GJIC by TNF alpha may provide an additional link between the processes of atherosclerosis and carcinogenesis. The protection afforded by antioxidant compounds suggests a role for active oxygen species in the promotion stage of atherosclerosis.

Antioxidants↗
PubMed1998

Inhibitory effect of pentachlorophenol on gap junctional intercellular communication in rat liver epithelial cells in vitro.

To understand the initiating/promoting actions of pentachlorophenol (PCP), a non-mutagenic hepatocarcinogen, and its metabolite, tetrachlorohydroquinone (TCHQ), we investigated the effects of each chemical on gap junctional intercellular communication (GJIC) in rat liver epithelial cells (WB cells) by the scrape-loading and dye transfer method. After treatment with PCP, the GJIC was initially inhibited at 4 h but was restored in 6-8 h, followed by a second phase of inhibition between 16 and 24 h. Both the first and second inhibitions were concentration-dependent and were restored by 2-4 h after removal of PCP. The phosphorylation state of connexin 43 (CX43) and its localization on the plasma membrane were unchanged up to 24 h after treatment; however, this was accompanied by a decrease in the CX43 protein level. No inhibitory effect was apparent on the GJIC of cells treated with TCHQ. These results suggest that PCP may play a critical role of promoting activity via non-mutagenic mechanisms.

Animals↗
PubMed1993

Heterologous gap junctional intercellular communication in normal and morphologically transformed colonies of Syrian hamster embryo cells.

A study was made of whether normal and morphologically transformed colonies in the Syrian hamster embryo (SHE) cell transformation assay performed heterologous gap junctional intercellular communication (GJIC). Two compounds, 12-O-tetradecanoylphorbol-13-acetate (TPA) and Na-orthovanadate (vanadate), which induce high frequencies of morphological transformation in SHE cells, have been employed. Three approaches were used to study the possibility of heterologous GJIC. (i) Morphologically transformed colonies (induced by TPA) partially overlapping with normal colonies were selected. Cells in the border area were micro-injected with the fluorescent dye Lucifer yellow to determine whether the dye spread to cells belonging to the other colony. This approach proved to be unsuccessful due to an inability to pinpoint which cells belonged to which colony. (ii) X-irradiated, non-dividing feeder cells are easily recognized by their large size. Feeder cells in contact with normal or TPA-transformed colonies were injected with Lucifer yellow. The dye was found to spread to most of the contacting cells, irrespective of whether they belonged to a normal or morphologically transformed colony. (iii) TPA- and vanadate-exposed colonies were labelled by endocytosis of Lucifer yellow overnight. This resulted in a punctate fluorescent pattern. Unlabelled, previously unexposed cells were seeded onto the dishes and incubated for 3.5-7 h. The ability to perform heterologous GJIC between the newly seeded cells and labelled colony cells was investigated. Both normal and transformed colonies were found to be able to communicate with the newly seeded cells. Thus, the present results indicate that selective communication is not a general property of morphologically transformed SHE cell colonies.

Animals↗
PubMed2004

Modulation of the HSV-TK/ganciclovir bystander effect by n-butyrate in glioblastoma: correlation with gap-junction intercellular communication.

The efficacy of HSV-TK/ganciclovir gene therapy largely relies on the bystander effect, i.e. the ability of transfected cells to kill the adjacent, untrasfected cells. This mechanism itself depends chiefly on the transfer via gap junctions of phosphorylated ganciclovir between cells, and is often deficient in glioblastomas. In this report, we demonstrate that n-butyrate markedly enhances the gap junction intercellular communication of GJIC-deficient glioma cells, and significantly increases the bystander effect in such cells. This effect of n-butyrate appears to be independent from its HDAC inhibitory effect, since trichostatin A does not reproduce it.

Butyrates↗
PubMed2003

Requirement of gap junctional intercellular communication for human villous trophoblast differentiation.

During pregnancy, the villous trophoblast develops from the fusion of cytotrophoblastic cells (CT) into a syncytiotrophoblast (ST), supporting the main physiological functions of the human placenta. Connexin43 (Cx43) is demonstrated in situ and in vitro in the villous trophoblast between CT and between CT and ST. Moreover, the presence of a gap junctional intercellular communication (GJIC) during in vitro trophoblast differentiation was previously demonstrated. Because the exchange of molecules through gap junctions is considered to play a major role in the control of cell and tissue differentiation, we studied the effects of a gap junctional uncoupler, heptanol, on morphological and functional trophoblast differentiation and on GJIC measured by the fluorescence recovery after photobleaching method. We found that when the GJIC was interrupted, CT still aggregated but fused poorly. This morphological effect was associated with a significant decrease of trophoblastic-specific gene expression (beta human chorionic gonadotropin and human chorionic somatomammotropin). This blocking action was reversible as demonstrated by recovery of GJIC and trophoblast differentiation process after heptanol removal. Moreover, the inhibition of the trophoblast differentiation did not affect Cx43 transcript expression and Cx43 protein expression. These data suggest that the molecular exchanges through gap junctions preceding cellular fusion are essential for trophoblast differentiation generating the multifunctional syncytiotrophoblast.

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↗
PubMed1992

Inhibition of gap-junctional intercellular communication by TPA and airborne particulate matter in primary cultures of rat alveolar type II cells.

Alveolar type II cells were isolated from the lungs of female Wistar rats and were used for studies on inhibition of gap junction mediated intercellular communication (IC). Cells were incubated with 12-O-tetradecanoylphorbol-13-acetate (TPA) or extracts of airborne particulate matter (APM) and subsequently microinjected with the fluorescent dye Lucifer Yellow after which the number of fluorescent (i.e. communicating) cells was determined. Cells exposed to solvent (DMSO), showed an extensive dye coupling. Exposure of cells to TPA or extracts of APM derived from different pollution sources resulted in a strong inhibition of IC. These results show that primary cultures of rat alveolar type II cells can serve pre-eminently as a model in dye-coupling experiments. It further can be concluded that extracts of APM, in addition to the genotoxic activity that has been known for many years, also may have a tumor-promoting potency.

Air Pollutants↗
PubMed2000

Preventive effect of epicatechin and ginsenoside Rb(2) on the inhibition of gap junctional intercellular communication by TPA and H(2)O(2).

The anticarcinogenic effects of epicatechin (EC) and ginsenoside Rb(2) (Rb(2)), which are major components of green tea and Korea ginseng, respectively, were investigated using a model system of gap junctional intercellular communication (GJIC) in WB-F344 rat liver epithelial cells. 12-O-tetradecanoylphorbol-13-acetate (TPA) and hydrogen peroxide, known as cancer promoters, inhibited GJIC in the epithelial cells as determined by the scrape loading/dye transfer assay, fluorescence redistribution assay after photobleaching, and immunofluorescent staining of connexin 43 using a laser confocal microscope. The inhibition of GJIC by TPA and H(2)O(2) was prevented with treatment of Rb(2) or EC. The effect of EC on GJIC was stronger in TPA-treated cells than in H(2)O(2)-treated cells, while the effect of Rb(2) was opposite to that of EC. EC, at the concentration of 27.8 microg/ml, prevented the TPA-induced GJIC inhibition by about 60%. Rb(2,) at the concentration of 277 microg/ml, recovered the H(2)O(2)-induced GJIC inhibition by about 60%. These results suggest that Rb(2) and EC may prevent human cancers by preventing the down-regulation of GJIC during the cancer promotion phase and that the anticancer effect of green tea and Korea ginseng may come from the major respective components, EC and Rb(2).

Animals↗
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↗
PubMed2005

Beta-sitosterol from psyllium seed husk (Plantago ovata Forsk) restores gap junctional intercellular communication in Ha-ras transfected rat liver cells.

We purified compounds from the husks of psyllium seeds (Plantago ovata Forsk; desert Indian wheat), beginning with an ethanol extraction then followed by HP-20 and silica gel chromatography, which restored gap junctional intercellular communication (GJIC) in v-Ha-ras transfected rat liver epithelial WB-F344 cell line (WB-Ha-ras). GJIC was assessed by a scrape loading dye transfer assay. The active compound was identified as beta-sitosterol based on gas chromatography retention times and electron ionization mass spectroscopy (EI-MS) spectrum of authentic beta-sitosterol. Authentic beta-sitosterol restored GJIC in the tumorigenic WB-Ha-ras GJIC-deficient cells at a dose of 2.4 microM. In addition, a similar phytosterol, stigmasterol, also restored GJIC, albeit at a lower activity. beta-sitosterol and stigmasterol increased the level of connexin43 protein (Cx43) and restored phosphorylation of Cx43 to levels similar to the parental nontransfected cell line. We concluded that the restoration of intercellular communication in the GJIC-deficient, tumorigenic WB-Ha-ras cell line by the ethanol soluble fraction of psyllium seed husks is largely due to the presence of the phytosterol, beta-sitosterol. We discuss implications for dietary modulation of cancer by beta-sitosterol.

Animals↗