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PubMed2004

Inhibition of gap junction intercellular communications in cell culture by polycyclic aromatic hydrocarbons (PAH) in the absence of PAH metabolism.

We have studied the effect of polycyclic aromatic hydrocarbons (PAH) on gap junction intercellular communications (GJIC) in culture of hepatoma cells Hep G2 and G27. Carcinogenic PAH inhibited GJIC in both cultures in contrast to non-carcinogenic PAH. We showed that both constitutive and inducible expressions of mRNAs of Ah receptor and cytochrome P4501A1 (the main isoform involved in PAH metabolism) were absent in hepatoma G27 cells. We concluded that the initial, non-metabolized molecules of carcinogenic PAH are responsible for changes in GJIC through interaction with an unknown factor in the cellular membrane.

Base Sequence↗

PubMed2004

Anisomycin downregulates gap-junctional intercellular communication via the p38 MAP-kinase pathway.

Phosphorylation of connexin 43 (Cx43) molecules (e.g. by extracellular signal-regulated kinase) leads to reductions in gap-junctional intercellular communication (GJIC). GJIC levels also appear to be lower in the presence of p38 mitogen-activated protein (MAP) kinase, for unknown reasons. In this study, we used assays of the recovery of fluorescence by photobleached WB-F344 cells to demonstrate that GJIC levels are decreased by anisomycin [a protein synthesis inhibitor as well as an activator of p38 MAP kinase and c-Jun N-terminal kinases (JNK)] as a result of time-dependent depletion of the phosphorylated forms of Cx43. Using immunohistochemistry, we also detected far less of the Cx43 proteins at cell borders. These findings agree with the photobleaching assay results. Moreover, prior treatment with SB203580 (a specific inhibitor of p38 MAP kinase) appeared to be effective in preventing the loss of phosphorylated forms of Cx43 and the loss of Cx43 proteins at cell borders. Total protein labelling with [(35)S]-methionine and [(32)P]-orthophosphates labelling of Cx43 showed that anisomycin enhanced the phosphorylation level of Cx43 along with inhibition of protein synthesis. SB203580 prevented the former but not the latter. The effect of anisomycin on GJIC was not dependent on the inhibition of protein synthesis because the addition of SB203580 completely maintained the level of GJIC without restoring protein synthesis. The Cx43 phosphorylation level increased by anisomycin treatment, whereas the amount of phosphorylated forms of Cx43 decreased, suggesting that activation of Cx43 phosphorylation might lead to the loss of Cx43. These results suggest that activation of p38 MAP kinase leads to reduction in the levels of phosphorylated forms of Cx43, possibly owing to accelerated degradation, and that these losses might be responsible for the reduction in numbers of gap junctions and in GJIC.

Animals↗

PubMed2001

Suppressed gap junctional intercellular communication in carcinogenesis of endometrium.

To examine whether and at which stage of endometrial carcinogenesis decreased connexin expression occurs, we investigated changes in the expression of the gap junction proteins, connexin 26 (Cx26), Cx32 and Cx43, in human endometrial hyperplasia and cancer samples. Forty-eight endometrial tissue samples (15 endometrial hyperplasias and 33 endometrial cancers) were subjected to immunofluorescence and RT-PCR analysis. In endometrial hyperplasia, Cx26 was aberrantly expressed in all samples as revealed immunohistochemically. There was weak or negative expression in 12 samples (80.0%) and diffuse expression in cytoplasm in 3 samples (20.0%). Cx32 expression in those samples was similar to that of Cx26; there was weak or negative expression in 11 samples (73.3%) and diffuse expression in 4 samples (26.7%). In endometrial cancer, Cx26 was expressed weakly or negatively in 25 samples (75.8%), diffusely in 6 samples (18.2%) and normally in 2 samples (6.1%), while Cx32 was expressed weakly or negatively in 26 samples (78.8%), diffusely in 5 samples (15.2%) and normally in 2 samples (6.1%). It was confirmed that weak staining of Cx26 and Cx32 was due to poor expression of their mRNA. All samples showed weak Cx43 protein expression as revealed by immunohistochemical analysis. In the majority of samples, concomitant expression levels of Cx26 and Cx32 protein were observed, confirming our long-term hypothesis that Cx26 and Cx32 are both abnormally regulated in a coordinated fashion in the endometrium. Our results indicate that during endometrial carcinogenesis, loss of gap junctional intercellular communication (GJIC) may occur due to the suppressed expression and the aberrant localization of connexin at relatively early stages.

Adenocarcinoma↗

PubMed2006

Noise magnetic fields abolish the gap junction intercellular communication suppression induced by 50 hz magnetic fields.

Previously, we have reported that exposure to 50 Hz coherent sinusoidal magnetic fields (MF) for 24 h inhibits gap junction intercellular communication (GJIC) in mammalian cells at an intensity of 0.4 mT and enhances the inhibition effect of 12-O-tetradecanoylphorbol-13-acetate (TPA) at 0.2 mT. In the present study, we further explored the effects of incoherent noise MF on MF-induced GJIC inhibition. GJIC was determined by fluorescence recovery after photobleaching (FRAP) with a laser-scanning confocal microscope. The rate of fluorescence recovery (R) at 10 min after photobleaching was adopted as the functional index of GJIC. The R-value of NIH3T3 cells exposed to 50 Hz sinusoidal MF at 0.4 mT for 24 h was 30.85 +/- 14.70%, while the cells in sham exposure group had an R-value of 46.36 +/- 20.68%, demonstrating that the GJIC of NIH3T3 cells was significantly inhibited by MF exposure (P < .05). However, there were no significant differences in the R-values of the sham exposure, MF-plus-noise MF exposure (R: 49.58 +/- 19.38%), and noise MF exposure groups (R: 46.74 +/- 21.14%) (P > .05), indicating that the superposition of a noise MF alleviated the suppression of GJIC induced by the 50 Hz MF. In addition, although MF at an intensity of 0.2 mT synergistically enhanced TPA-induced GJIC inhibition (R: 24.90 +/- 13.50% vs. 35.82 +/- 17.18%, P < .05), further imposition of a noise MF abolished the synergistic effect of coherent MF (R: 32.51 +/- 18.37%). Overall, the present data clearly showed that although noise MF itself had no effect on GJIC of NIH3T3 cells, its superposition onto a coherent sinusoidal MF at the same intensity abolished MF-induced GJIC suppression. This is the first report showing that noise MF neutralizes 50 Hz MF-induced biological effect by using a signaling component as the test endpoint.

Animals↗

PubMedDate not supplied

The relationship between gap-junctional intercellular communication and the proliferative activity of retinal pigment epithelial cells.

PURPOSE: To investigate the relationship between gap-junction mediated intercellular communication and the proliferative activity of retinal pigment epithelial cells in the retinal tear base. METHODS Retinal tears were created experimentally in white rabbits, and the changes of intercellular communication via gap junctions between retinal pigment epithelial cells in the retinal tear base were investigated using the dye-coupling method, which involves observing the spread of a fluorescent dye, Lucifer Yellow CH. In addition, the proliferative activity of these cells was investigated using an antibody for proliferating cell nuclear antigen and was compared with the changes in intercellular communication. RESULTS: Immediately after the creation of retinal tears, extensive spreading of Lucifer Yellow CH into adjacent cells was observed, which was markedly reduced 1 week later. After 1 month, the spreading of dye to adjacent cells was observed again. On the other hand, proliferative activity was enhanced at 1 week after retinal tear creation and was reduced again after 1 month. CONCLUSIONS: It is known that tumor cells with enhanced proliferative activity show decreased intercellular communication via gap junctions. The present study suggests a possible relationship between intercellular communication and the proliferative activity of retinal pigment epithelial cells in the base of retinal tears.

Animals↗

PubMed1996

Inhibition of gap junctional intercellular communication by barbiturates in long-term primary cultured rat hepatocytes is correlated with liver tumour promoting activity.

Rodent liver tumor formation can be promoted by certain barbiturates and this may involve their ability to inhibit hepatocyte gap junctional intercellular communication (GJIC). In order to address the mechanisms and specificity of action of barbiturates on hepatocyte gap junctions, we have compared the effects of liver tumor-promoting barbiturates (phenobarbital, sodium barbital and amobarbital: PB, SB and AB, respectively) and a non-liver tumor-promoting barbiturate (barbituric acid: BA) on primary cultured rat hepatocyte GJIC and connexin32 (Cx32) expression after short (1-24 h) and long (2-14 days) treatment. GJIC was evaluated by fluorescent dye microinjection (dye-coupling); Cx32 expression was monitored by Northern blot, Western blot and immunohistochemistry. Both parameters were maintained at high levels over 14 days by coculture of the cells with WB-F344 rat liver epithelial cells in the presence of dexamethasone. Treatment with PB (2 mM) for 1 h sharply reduced dye-coupling from approximately 90-30%, but the cells fully recovered by 24 h. No inhibition was seen with the other barbiturates over this 1-day treatment period. Longer treatments (2-14 days) with the promoters PB, SB and AB, however, gradually reduced hepatocyte dye-coupling to approximately 30-50%. The non-promoter, BA, did not affect hepatocyte GJIC. These decreases in hepatocyte dye-coupling occurred without changes in Cx32 or gap junction expression. Dye-coupling of WB-F344 cells and expression of their predominant gap junction protein, connexin43 (Cx43), were also not affected. Thus, the inhibition of GJIC was specific to liver tumor promoting barbiturates in hepatocytes, was time-dependent and was not due to altered Cx32 expression.

Animals↗

PubMed2003

Endothelin-1 decreases gap junctional intercellular communication by inducing phosphorylation of connexin 43 in human ovarian carcinoma cells.

Endothelin-1 (ET-1) is overexpressed in ovarian carcinoma and acts as an autocrine factor selectively through the ETA receptor (ETAR) to promote tumor cell proliferation, survival, neovascularization, and invasiveness. Loss of gap junctional intercellular communication (GJIC) is critical for tumor progression by allowing the cells to escape growth control. Exposure of HEY and OVCA 433 ovarian carcinoma cell lines to ET-1 led to a 50-75% inhibition in intercellular communication and to a decrease in the connexin 43 (Cx43)-based gap junction plaques. To investigate the phosphorylation state of Cx43, ovarian carcinoma cell lysates were immunoprecipitated and transient tyrosine phosphorylation of Cx43 was detected in ET-1-treated cells. BQ 123, a selective ETAR antagonist, blocked the ET-1-induced Cx43 phosphorylation and cellular uncoupling. Gap junction closure was prevented by tyrphostin 25 and by the selective c-Src inhibitor, PP2. Furthermore, the increased Cx43 tyrosine phosphorylation was correlated with ET-1-induced increase of c-Src activity, and PP2 suppressed the ET-1-induced Cx43 tyrosine phosphorylation, indicating that inhibition of Cx43-based GJIC is mainly mediated by the Src tyrosine kinase pathway. In vivo, the inhibition of human ovarian tumor growth in nude mice induced by the potent ETAR antagonist, ABT-627, was associated with a reduction of Cx43 phosphorylation. These findings indicate that the signaling mechanisms involved in GJIC disruption on ovarian carcinoma cells depend on ETAR activation, which leads to the Cx43 tyrosine phosphorylation mediated by c-Src, suggesting that ETAR blockade may contribute to the control of ovarian carcinoma growth and progression also by preventing the loss of GJIC.

Animals↗

PubMed1994

Inhibition of gap junctional intercellular communication in Syrian hamster embryo cells by TPA, retinoic acid and DDT.

12-O-Tetradecanoylphorbol-13-acetate (TPA), trans-retinoic acid (RA) and DDT inhibit gap junctional intercellular communication in Syrian hamster embryo (SHE) cells. The inhibition is rapid and takes place within minutes. Northern blot analysis shows that SHE cells express connexin 43 and that exposure to these compounds for up to 20 h has no effect on connexin 43 mRNA level. Immune cytochemistry shows that the connexon structures in SHE cells are scattered over the cell, and not confined to the cell-cell boundaries as is the case in the rat liver epithelial cell line IAR20. RA and TPA induce the disappearance of the connexon structures in parallel to the induced inhibition of communication in SHE cells. The disappearance of the connexon spots takes place with no apparent effect on the cellular content of connexin protein measured by immunoblotting, and is probably caused by disaggregation of the connexon structures rather than disappearance or degradation of the connexin protein. DDT shows little or no apparent effect on connexin immunostaining in SHE cells, indicating a different mechanism of action. In the IAR20 cells, exposure to TPA and RA also results in loss of immunostainable connexon structures while exposure to DDT results in relocalization of the connexons away from the cell-cell borders. Immunoblotting of connexin 43 in SHE cells results in three major bands with apparent mol. wts of 40-50 kDa where the two higher mol. wt bands represent phosphorylated connexin 43 protein. Exposure of the cells to the communication inhibiting compounds results in reduction or loss of the highest mol. wt phosphorylated band, indicating a relation between a specific connexin phosphorylation and aggregation of connexin 43 protein to functional communicating gap junctions. The results suggest the presence of various post-transcriptional control mechanisms in the regulation of connexin function which are vulnerable to exogenous stimuli.

Animals↗

PubMed2004

Breast cancer metastatic potential: correlation with increased heterotypic gap junctional intercellular communication between breast cancer cells and osteoblastic cells.

The breast cancer metastasis-suppressor gene BRMS1 is downregulated in metastatic breast cancer cells. Previous reports have shown restoration of gap junctional intercellular communication (GJIC) in the metastatic human breast carcinoma cell line MDA-MB-435 (435) transfected with BRMS1 cDNA. Metastasis, to a large extent in most breast cancers, occurs to bone. However, the reason for this preferential metastasis is not known. We explored cell-to-cell communication between 435 carcinoma cells and a human osteoblastic cell line, hFOB1.19, to determine whether carcinoma cells can form gap junctions with bone cells and to explore the role of these heterotypic gap junctions and the BRMS1 gene in breast cancer metastasis to bone. 435 cells displayed greater cell-to-cell communication with hFOB 1.19 cells than with themselves. Transfection of BRMS1 into 435 cells increased homotypic gap junctional communication but did not significantly affect heterotypic communication with hFOBs. However, heterotypic communication of BRMS1 transfectants with hFOB cells was reduced relative to homotypic communication. In contrast, parental 435 cells displayed greater heterotypic communication with hFOBs relative to homotypic communication. Our results suggest that there are differences in the relative homotypic and heterotypic GJIC of metastasis-capable and -suppressed cell lines.

Bone Neoplasms↗

PubMed1998

Inhibition of intrinsic gap-junction intercellular communication and enhancement of tumorigenicity of the rat bladder carcinoma cell line BC31 by a dominant-negative connexin 43 mutant.

The tumor-suppressive property of the connexin gap-junction proteins was postulated from the fact that their function of cell coupling is impaired in most cancer cells. However, in conflict with this notion, certain cancer cells are able to communicate through gap junctions despite their malignancy. To explain this phenomenon, we studied by using a dominant-negative strategy the effect on tumorigenicity of loss of intrinsic gap-junction intercellular communication (GJIC) in the rat bladder carcinoma cell line BC31, which shows both expression of connexin 43 (Cx43) and intercellular communication. In cells transfected with a mutant Cx43 with seven residues deleted from the internal loop at positions 130-136 (Cx43delta), transport of the resulting connexin protein to the plasma membrane occurred normally, but the GJIC of the cells was effectively abolished at the level of permeability of established gap junctions. Dominant-negative inhibition of GJIC by Cx43delta accelerated growth of BC31 cells in nude mice. In contrast, when GJIC in BC31 cells was artificially enforced by transfection of wild-type Cx43, the cells lost the capacity to grow in vivo. Decreased phosphorylation of Cx43delta suggested close interaction of the internal loop of connexin with its commonly phosphorylated domains in the C-terminal tail and involvement of this interaction in gap-junction permeability. Therefore, we conclude that the intrinsic GJIC observed in cancer cells should be considered a tumor-suppressor factor and that its level may influence malignant growth capacity.

Animals↗

PubMed2003

Gap junctional intercellular communication in cells isolated from urethane-induced tumors in A/J mice.

Studies using normal or neoplastically transformed established mouse lung epithelial cell lines revealed a reduction in gap junctional, intercellular communication (GJIC) with transformation. To determine the stage in tumor development at which GJIC is interrupted, we used the well-established model of lung tumors induced in strain A/J mice by urethane. In this system, tumor development follows a well-characterized pattern; hyperplasias, adenomas, and carcinomas are manifested at approximately 8, 16, and 40 weeks after urethane treatment, respectively. GJIC levels were examined using a novel technique where cells are grown on a glass slide, half of which is coated with electrically conductive, optically transparent, indium-tin oxide. An electric pulse that opens transient pores on the plasma membrane is applied in the presence of the fluorescent dye, Lucifer yellow, causing dye penetration into cells growing on the conductive part of the slide. Migration of the dye through gap junctions to nonelectroporated cells growing on the nonconductive area is then microscopically observed under fluorescence illumination. Unexpectedly, primary cells cultured from urethane-induced tumors, even late stage carcinomas, possessed extensive GJIC immediately upon isolation. Upon passage for several months however, these cells lost GJIC. These results suggest that the molecular changes that lead to the formation of the tumor in vivo are not sufficient to interrupt gap junctions. Propagation of tumor cells in culture induces additional alterations that can lead to gap junction closure.

Animals↗

PubMed2003

Lysosomal and proteasomal degradation play distinct roles in the life cycle of Cx43 in gap junctional intercellular communication-deficient and -competent breast tumor cells.

The present study was designed to determine the specific roles played by lysosomes and proteasomes in the degradation of Cx43 in both gap junctional intercellular communication-deficient MDA-MB-231 and -competent BICR-M1Rk cells. In MDA-MB-231 cells, immunolocalization and brefeldin A protein transport blocking studies revealed that there was a propensity for newly synthesized Cx43 to be transported to lysosomes. On the other hand, light and electron microscopic analysis of BICR-M1Rk cells showed that Cx43 gap junctions were prevalent with a subpopulation of intracellular Cx43 localized to lysosomes. In both cell types, Western blots revealed a notable increase in total cellular Cx43 in response to lysosome inhibitors. Interestingly, lactacystin inhibition of proteosomal degradation in MDA-MB-231 cells resulted in a marked increase in phosphorylated Cx43 at the expense of non-phosphorylated Cx43, and this change corresponded with an increase in "oversized" gap junction plaques. In BICR-M1Rk cells, lactacystin treatment partially prevented the BFA-induced loss of gap junctions. Together, our data suggests that lysosomes play a key role in not only degrading internalized gap junction in BICR-M1Rk cells but also in degrading Cx43 delivered from early secretory compartments to lysosomes in MDA-MB-231 cells. Overall proteasomal degradation regulates the stability of phosphorylated Cx43 and appears to promote the internalization of Cx43 from the cell surface.

Acetylcysteine↗

PubMed1998

Induction of cell transformation by mutated 16K vacuolar H+-atpase (ductin) is accompanied by down-regulation of gap junctional intercellular communication and translocation of connexin 43 in NIH3T3 cells.

The 16 K subunit of the vacuolar H+-ATPase (ductin) has been suggested to also play a role in gap junction channels. Since mutated 16 K subunits have transforming ability when transfected into NIH3T3 cells and since aberrant gap junctional intercellular communication (GJIC) is a hallmark of cancer cells, we hypothesized that mutated 16 K subunits might transform these cells via alteration of GJIC. When GJIC was measured by the dye-transfer assay, NIH3T3 cells transfected with the mutant 16 K protein genes (deletion of the fourth transmembrane domain or a point mutation at codon 143 from glutamic acid to arginine) showed significantly lower levels of GJIC than those transfected with the vector alone or with the wild-type 16 K subunit gene. GJIC levels of NIH3T3 cells transformed by v-ras and v-src were not significantly decreased, suggesting that low GJIC levels are not necessarily the result of cell transformation per se. NIH3T3 cells express C x 43 as a major connexin gene. Although cells transfected with mutated 16 K subunits showed a level of C x 43 protein expression similar to non-transfectants, their C x 43 protein was localized aberrantly, i.e. intracytoplasmically. These results indicate that mutant 16 K subunits with transforming ability translocate C x 43 proteins, thus inhibiting GJIC of NIH3T3 cells.

3T3 Cells↗

PubMed1998

[A study on dose-effect of suppression to gap junctional intercellular communication function by 50-Hz magnetic fields].

OBJECTIVE: To study the relationship between dose of exposure to 50-Hz magnetic field (MF) and its effects of suppression to gap junctional intercellular communication (GJIC) function. METHODS: Lucifer yellow, a kind of fluorescent dye, was led into single CHL cell by iontophoretic injection. Number of dye-coupled cells (DCC) five minutes after injection was used as an indicator for GJIC function. The effects of different intensities and irradiation of MF on GJIC in CHL cells were studied. RESULTS: Suppression to GJIC by 50-Hz MF depended on its flux intensity. Irradiation with lower flux intensity (0.05, 0.2 and 0.4 mT) of the MF for 24 hours could not inhibit GJIC, but that with higher intensity (0.8 and 1.6 mT) could. No "amplitude window" effect was appeared by irradiation with MF at intensities of zero to 1.6 mT. Exposure to MF at a fixed intensity of 0.8 mT for five minutes had no effects, but that for one hour was more than enough to inhibit GJIC, with the most apparent effects for 24-hour exposure. In addition, it was showed that suppression to GJIC was caused by direct action of 50-Hz MF rather then induced electrical field. CONCLUSION: MF of 50-Hz had suppression to GJIC with a dose-effect relationship.

Animals↗

PubMed2006

[The cytotoxicity of nickel-refining dusts for chinese hamster lung cells and effects on gap junctional intercellular communication].

OBJECTIVE: To investigate the cytotoxicity of the nickel-refining dusts for Chinese hamster lung (CHL) cells and the effects of nickel-refining dusts on the gap junctional intercellular communication (GJIC) of CHL cells. METHODS: The cytotoxicity of the nickel-refining dusts for the CHL cells was determined in two nickel-refining dusts samples with the CHL cells as the target cells by MTT method while the effects of nickel-refining dusts on the CJIC of the CHL cells were investigated using the scrape-loading and dye transfer (SLDT) technique. RESULTS: There were no significant difference in the CHL proliferation between all dosage groups in the two samples and the control group at 6 and 12 hours (P > 0.05). The survival rate of cells in all dosage groups were all decreased at 36 hours (P < 0.05), presenting the dosage-reaction relationship and the time-reaction relationship. IC(50) was 21.36 and 23.07 micro/ml for the two samples respectively at 36 hours. Compared with the control group, the transport of Lucifer Yellow (LY) from the injury line to the adjacent cells was decreased when the CHL cells were treated with nickel-refining dusts of 25.00, 50.00 and 100.00 microg/ml (P < 0.01). CONCLUSION: The nickel-refining dusts have cytotoxicity for the CHL cells cultivated in vitro, can inhibit the growth of the cells and at a certain concentration can inhibit the GJIC function of CHL cells.

Animals↗

PubMed2001

Upregulation of gap junctional intercellular communication and connexin 43 expression by cyclic-AMP and all-trans-retinoic acid is associated with glutathione depletion and chemosensitivity in neuroblastoma cells.

PURPOSE: Downregulation of gap junctional intercellular communication (GJIC) has been implicated in carcinogenesis. This is a result of altered expression of connexins, the proteins that mediate GJIC, including connexin 43 (Cx43). Our aim was to evaluate the effect of known inducers of Cx43 on the chemosensitivity of the human neuroblastoma cell line IMR-32 to chemotherapeutic agents. METHODS: We examined the effect of dibutyryl-cyclic AMP (db-cAMP) and all-trans-retinoic acid (tRA) on Cx43 and GJIC, glutathione (GSH) and gamma-glutamyl-cysteine-synthetase (gamma-GCS) levels, and glutathione S-transferase (GST) activity. Finally, we performed cell survival assays to measure the response of IMR-32 cells to the chemotherapeutic drugs doxorubicin, melphalan and bis-chloronitrosourea (BCNU), after treatment with db-cAMP and/or tRA. RESULTS: Exposure to db-cAMP led to the upregulation of GJIC and Cx43 expression and phosphorylation. On the other hand, exposure to tRA led to the upregulation of GJIC but Cx43 expression and phosphorylation were not greatly affected. The combination of both agents was more potent in inducing GJIC in comparison to treatment with db-cAMP or tRA alone. Treatment with db-cAMP, but not with tRA, was associated with a significant increase in the cytotoxic effects of the anticancer drugs doxorubicin, melphalan and BCNU as shown by a decrease in their IC50 values. Concomitant exposure to db-cAMP and tRA, however, had a more pronounced effect on cell sensitization to chemotherapy drugs (particularly doxorubicin) than exposure to db-cAMP or tRA alone. Under the db-cAMP and tRA treatment conditions (which upregulate GJIC and modulate drug response), GSH levels were significantly reduced while the levels of GST and gamma-GCS activities remained unchanged. CONCLUSIONS: This study suggests that GJIC plays a role in cellular drug resistance, and highlights the potential use of GJIC modulators in combination with chemotherapy. Also, this is the first study exploring the ability of both db-cAMP and tRA to enhance cell chemosensitivity.

Bucladesine↗

PubMed1996

Inhibition of gap junctional intercellular communication and delocalization of the cell adhesion molecule E-cadherin by tumor promoters.

The effect of 12-O-tetradecanoylphorbol-13-acetate (TPA) and benzoyl peroxide (BoP) on gap junctional intercellular communication (GJIC) and the amount and localization of E-cadherin was studied in initiated mouse epidermal cells (3PC) and in carcinoma cells (CA3/7) originating from the same cell type. In addition, the localization and phosphorylation of connexin43 was studied in both cell lines and in primary keratinocytes. GJIC inhibition by TPA and BoP was stronger in primary keratinocytes compared with both cell lines. BoP strongly decreased the amount of E-cadherin protein and the level occurring in the membranes in both cell lines, whereas TPA caused a translocation of E-cadherin from the membrane towards the cytosol, without decreasing the total amount of E-cadherin present. The effect of both tumor promoters on connexin43 phosphorylation and localization was agent as well as cell dependent. These results show for the first time that tumor promoters can decrease the quantity and membrane localization of E-cadherin in different cell types.

Animals↗

PubMed2000

Effects of Di-2-ethylhexyl phthalate (DEHP) on gap-junctional intercellular communication (GJIC), DNA synthesis, and peroxisomal beta oxidation (PBOX) in rat, mouse, and hamster liver.

The present study evaluated the effect of di-2-ethylhexyl phthalate (DEHP) on gap-junctional intercellular communication (GJIC), peroxisomal beta-oxidation (PBOX) activity, and replicative DNA synthesis in several rodent species with differing susceptibilities to peroxisome proliferator-induced hepatic tumorigenesis. A low (non-tumorigenic) and high (tumorigenic) dietary concentration of DEHP was administered to male F344 rats for 1, 2, 4, and 6 weeks. Additionally, a previously non-tumorigenic dose (1000 ppm) and tumorigenic dose of DEHP (12,000 ppm), as determined by chronic bioassay data, were examined following 2 weeks dietary administration. Male B6C3F1 mice were fed the non-tumorigenic concentration, 500 ppm, and the tumorigenic concentration, 6000 ppm, of DEHP for two and four weeks. The hepatic effects of low and high concentrations of DEHP, 1000 and 6000 ppm, were also examined in male Syrian Golden hamsters (refractory to peroxisome proliferator-induced tumorigenicity). In rat and mouse liver, a concentration-dependent increase in the relative liver weight, PBOX activity, and replicative DNA synthesis was observed at the earliest time point examined. Concurrent to these observations was an inhibition of GJIC. In hamster liver, a slight increase in the relative liver weight, PBOX activity, and replicative DNA synthesis was observed. However, these effects were not of the same magnitude or consistency as those observed in rats or mice. Furthermore, DEHP had no effect on GJIC in hamster liver at any of the time points examined (2 and 4 weeks). HPLC analysis of DEHP and its primary metabolites, mono-2-ethylhexyl phthalate (MEHP), and phthalate acid (PA), indicated a time- and concentration-dependent increase in the hepatic concentration of MEHP. At equivalent dietary concentrations and time points, the presence of MEHP, the primary metabolite responsible for the hepatic effects of DEHP, demonstrated a species-specific response. The largest increase in the hepatic concentration of MEHP was observed in mice, which was greater than the concentration observed in rats. The hepatic concentration of MEHP was lowest in hamsters. Hepatic concentrations of DEHP and phthalic acid were minimal and did not correlate with concentration and time. Collectively, these data demonstrate the inhibition of hepatic GJIC and increased replicative DNA synthesis correlated with the observed dose- and species-specific tumorigenicity of DEHP and may be predictive indicators of the nongenotoxic carcinogenic potential of phthalate esters.

Animals↗