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PubMed1997

Triazine derivatives inhibit rat hepatocarcinogenesis but do not enhance gap junctional intercellular communication.

We report here novel candidate chemopreventive agents active against experimental hepatocarcinogenesis. The triazine derivatives 6-(2-chlorophenyl)-2,4-diamino-1,3,5-triazine (2CPDAT), 6-(3-chlorophenyl)-2,4-diamino-1,3,5-triazine (3CPDAT), 6-(4-chlorophenyl)-2,4-diamino-1,3,5-triazine (4CPDAT), 6-(4-pyridyl)-2,4-diamino-1,3,5-triazine (PyDAT), and 6-(pyridine N-oxid-4-yl)-2,4-diamino-1,3,5-triazine (PyNODAT), synthesized in our laboratory, in addition to 6-(2,5-dichloro-phenyl)-2,4-diamino-1,3,5-triazine (DCPDAT), or irsogladine, which is a widely used anti-ulcer drug, were investigated for potential chemopreventive effects in a rat liver medium-term bioassay system. A significant inhibitory influence on enzyme-altered liver foci was found for 2CPDAT, 3CPDAT, 4CPDAT, and PyNODAT, but not for DCPDAT or PyDAT. The involvement of gap junctional intercellular communication in the inhibition was studied, but no change in gap junctional intercellular communication capacity in rat liver cells in vitro or in gap junction protein (connexin 32) expression in rat liver in vivo was noted. These results indicate that, although these irsogladine analogues exert inhibitory effects on rat liver carcinogenesis, their action is independent of modification of gap junctional intercellular communication.

Animals↗
PubMed1990

Modulation of intercellular communication during radiation and chemical carcinogenesis.

Carcinogenesis is a multistep process, involving the irreversible conversion of a stem cell to a terminal-differentiation-resistant cell ("initiation"), followed by the clonal expansion of this cell ("promotion") and by the acquisition of other genetic alterations leading to malignancy ("progression"). The initiation and progression steps seem to be facilitated by mutagenesis. Promotion has been associated with agents and conditions that cause mitogenesis. Gap junctional intercellular communication, a fundamental biological process regulating cell growth and differentiation, has been postulated to play a major role in carcinogenesis. The hypothesis is supported by the fact that many cancer cells have some dysfunction in gap junctional intercellular communication, many tumor-promoting chemicals and several oncogenes (i.e., ras, src, mos, neu, but not myc) reduce gap junctional intercellular communication, and several growth factors (i.e., EGF, TGF-beta, bovine pituitary extract) inhibit gap junction function. This integrative concept postulates that chemical promoters, oncogenes coding for growth factors, receptors, or transmembrane signaling elements, and growth factors can isolate an initiated cell from the suppressing influence of surrounding normal cells by down-regulating the transfer of ions and small molecules through gap junctions.

Animals↗
PubMedDate not supplied

Effects of neuroinflammation on glia-glia gap junctional intercellular communication: a perspective.

Gap junctions serve as intercellular conduits that allow for the direct transfer of small molecular weight molecules (up to 1 kDa) including ions involved in cellular excitability, metabolic precursors, and second messengers. The observation of extensive intercellular coupling and large numbers of gap junctions in the central nervous system (CNS) suggests a syncytium-like organization of glial compartments. Inflammation is a hallmark of various CNS diseases such as bacterial and viral infections, multiple sclerosis, Alzheimer's disease, and cerebral ischemia. A general consequence of brain inflammation is reactive gliosis typified by astrocyte hypertrophy and proliferation of astrocytes and microglia. Changes in gap junction intercellular communication as reflected by alterations in dye coupling and connexin expression have been associated with numerous CNS inflammatory diseases, which may have dramatic implications on the survival of neuronal and glial populations in the context of neuroinflammation. A review of the effects of inflammatory products on glia-glia gap junctional communication and glial glutamate release is presented. In addition, the hypothesis of a "syncytial switch" based upon differential regulation of gap junction expression in astrocytes and microglia during normal CNS homeostasis and neuroinflammation is proposed.

Animals↗
PubMed1967

Intercellular communication and tissue growth. I. Cancerous growth.

Intercellular communication was examined with intracellular electrical techniques in primary and transplanted rat liver cancers. Normal liver cells communicate rather freely with each other through permeable junctional membranes. Cancer liver cells show no communication at all; their surface membrane is a strong barrier to diffusion all around the cell. Cancer cells induce alterations in membrane permeability in normal liver cells; communication among the latter is markedly reduced when cancer cells grow near them.

Animals↗
PubMed1967

Intercellular communication and tissue growth. II. Tissue regeneration.

Intercellular communication was examined in regenerating rat liver and urodele skin, two tissues of fast but normal growth. In both, cellular communication is in general as good as in their respective normal intact state. This stands in striking contrast to the lack of cellular communication in tissues with cancerous growth. Upon wounding of the urodele skin, the normally permeable junctional membranes of cells near the wound border seal themselves off, thereby insulating the interiors of the communicated cell systems from the exterior. When the cells of two opposing borders make mechanical contact in the course of wound closure, communication between them ensues within 30 min. Within this period all cell movement also ceases ("contact inhibition"). The possible implications of these findings in the control of tissue growth are discussed.

Animals↗
PubMed1968

Intercellular communication and tissue growth. 3. Thyroid cancer.

Intercellular communication was examined in normal and cancerous isolated thyroids with an intracellular electrical technique. The cells of normal thyroid (rat, mouse, hamster, man) communicate, within any given follicle, through permeable junctions. The cells of a wide variety of thyroid cancers (rat, hamster) do not communicate to any detectable degree and have resting membrane potentials lower than those of normal cells.

Animals↗
PubMed1997

Changes in gap junctional intercellular communication in mouse skin carcinogenesis.

Gap junction intercellular communication (GJIC) has been measured in cell lines that represent different stages of chemically induced mouse skin carcinogenesis. No significant difference in GJIC, as measured by dye spread, was found in cultures of normal keratinocyte, papilloma or squamous carcinoma cell lines. There was no correlation, in this system, between the presence of a mutant Ha-ras gene and down-regulation of communication. There was, however, a marked decrease in GJIC (80-90%) on progression from squamous to spindle carcinoma cells. Measurement of GJIC in somatic cell hybrids shows that the genetic defect responsible for this down-regulation is recessive and is common to two independently isolated spindle cell lines. No abnormalities were found in the spindle cells in expression of connexin 43, a cell component involved in gap junction formation and permeability. However, expression of E-cadherin, a cell-cell adhesion molecule implicated in the process of gap junction formation, was missing in the spindle carcinoma cells. Introduction of an E-cadherin cDNA into the spindle cells partially restored junctional communication without causing any noticeable alterations in cell morphology. During the study a non-tumourigenic keratinocyte line, a sub-clone of a normal keratinocyte line, was also found to have a low level of GJIC. However, the defect in this line was shown, by genetic complementation in somatic cell hybrids, to be different from that in the spindle carcinoma cell lines. Consistent with these data, analysis by immunofluorescence shows an abnormal distribution of connexin 43 in these cells.

Animals↗
PubMed1987

Selective lack of intercellular communication between transformed and nontransformed cells as a common property of chemical and oncogene transformation of BALB/c 3T3 cells.

BALB/c 3T3 cells can be transformed by transfection of an activated cellular oncogene as well as by chemicals. When the cells were transformed by pEJ-ras transfection, a marked increase in Mr 21,000 protein expression was found by Western blotting and immunohistochemical staining, whereas no such increase was detected in cells transformed by methylcholanthrene, suggesting two different molecular mechanisms. By directly microinjecting a fluorescent dye (Lucifer Yellow CH) into individual cells, we measured junctional intercellular communication among and between transformed and surrounding nontransformed cells. In both chemical and oncogene transformation studies, transformed cells and surrounding normal cells have similar capacities for gap-junctional communication, but there was complete lack of communication between transformed and nontransformed cells. When BALB/c 3T3 cells were transformed by methylcholanthrene initiation followed by phorbol ester promotion, again we saw no intercellular communication between transformed and nontransformed cells, suggesting that the observed selective communication block between transformed and nontransformed cells may be a general phenomenon in BALB/c 3T3 cells. These results indicate that selective lack of intercellular communication between transformed and surrounding normal cells may be an important phenomenon that separates transformed cells and nontransformed cells, permitting transformed cells to maintain autonomous growth.

Cell Communication↗
PubMed2006

Regulation of IL-8 by Irsogladine maleate is involved in abolishment of Actinobacillus actinomycetemcomitans-induced reduction of gap-junctional intercellular communication.

Our previous report has shown that Irsogladine maleate (IM) counters and obviates the reduction in gap junction intercellular communication (GJIC) and the increase in IL-8 levels, respectively, induced by outer membrane protein 29 from Actinobacillus actinomycetemcomitans (A. actinomycetemcomitans) in cultured human gingival epithelial cells (HGEC). In addition, IM suppresses the increase in the secretion of IL-8 caused by whole live A. actinomycetemcomitans. These findings implicate the modulation of IL-8 levels by IM in abolishment of the reduction of GJIC in HGEC. Tight junctions are also responsible for cell-cell communication. Zonula occludens protein-1 (ZO-1) is a major tight junction protein. To investigate the regulatory mechanism of intercellular communication mediated by IM, in the present study, we focused on the involvement of IL-8 in A. actinomycetemcomitans-induced change in GJIC and ZO-1 expression in HGEC. IM countered the A. actinomycetemcomitans-induced reduction in levels of Connexin (CX) 43, suggesting that it could abolish the A. actinomycetemcomitans-induced reduction in GJIC in HGEC. CXCR-1 is a receptor of IL-8. The simultaneous addition of A. actinomycetemcomitans and anti-CXCR-1 antibody also abrogated the repression of GJIC and CX43 expression by A. actinomycetemcomitans in HGEC, although the anti-CXCR-1 antibody was less effective than IM. IM inhibited the IL-8-induced reduction in CX43 levels and GJIC in HGEC. IM countered the A. actinomycetemcomitans-induced reduction in the expression of ZO-1, although anti-CXCR-1 antibody did not influence the decrease in ZO-1 mRNA levels caused by A. actinomycetemcomitans. Furthermore, IL-8 had little effect on the mRNA levels of ZO-1. These findings suggest that IL-8 mediates the A. actinomycetemcomitans-induced reduction of GJIC and CX43 expression in HGEC. The regulation of IL-8 levels by IM in HGEC is partially involved in abrogation of the reduction of GJIC and CX43 expression by A. actinomycetemcomitans. Furthermore, the regulatory effect of IM on the expression of CX43 and ZO-1 is different.

Aggregatibacter actinomycetemcomitans↗
PubMed1994

Is intercellular communication via gap junctions required for myoblast fusion?

Fusion of myoblasts to form syncitial muscle cells results from a complex series of sequential events including cell alignment, cell adhesion and cell communication. The aim of the present investigation was to assess whether intercellular communication through gap junctions would be required for subsequent membrane fusion. The presence of the gap junction protein connexin 43 at areas of contact between prefusing rat L6 myoblasts was established by immunofluorescent staining. These myoblasts were dye-coupled, as demonstrated by the use of the scrape-loading/dye transfer technique. L6 myoblast dye coupling was reversibly blocked by heptanol in short term experiments as well as after chronic treatment. After a single addition of 3.5 mM heptanol, gap junctions remained blocked for up to 8 hours, then this inhibitory effect decreased gradually, likely because the alcohol was evaporated. Changing heptanol solutions every 8 hours during the time course of L6 differentiation resulted in a lasting drastic inhibition of myoblast fusion. We further investigated the effect of heptanol and of other uncoupling agents on the differentiation of primary cultures of embryonic chicken myoblasts. These cells are transiently coupled by gap junctions before myoblast fusion and prolonged application of heptanol, octanol and 18-beta-glycyrrhetinic acid also inhibited their fusion. The effect of heptanol and octanol was neither due to a cytotoxic effect nor to a modification of cell proliferation. Moreover, heptanol treatment did not alter myoblast alignment and adhesion. Taken together these observations suggest that intercellular communication might be a necessary step for myoblast fusion.

Alcohols↗
PubMed1989

Gap-junctional intercellular communication in epidermal cell lines from selected stages of SENCAR mouse skin carcinogenesis.

Homologous and heterologous gap-junctional intercellular communication (IC) was characterized in a panel of cell lines derived from selected stages of SENCAR mouse skin carcinogenesis. This panel included a "carcinogen-altered" cell line, 3PC, obtained from Ca2+-resistant primary adult keratinocytes after exposure to dimethylbenz(a)anthracene as well as cell lines obtained from early and late-stage papillomas and a squamous cell carcinoma (CA3/7) generated during standard in vivo initiation/promotion protocols (dimethylbenz(a)anthracene/12-O-tetradecanoyl-phorbol-13-acetate). Also studied was a cell line (B66BA) obtained from a metastatic lesion following benzo(a)pyrene-induced skin tumorigenesis. Intercellular communication was measured in low-calcium (0.05 mM) medium by quantitation of cell-cell transfer of microinjected fluorescent dye Lucifer Yellow CH. Homologous IC ability diminished progressively from 68 dye-coupled cells per injection for 3PC cultures, to between 21 and 54 dye-coupled cells per injection for three papilloma-derived cell lines, to six and three dye-coupled cells per injection for CA3/7 and B66BA cells, respectively. To test communication of these cells with their normal counterparts, heterologous IC was examined in cocultures with primary adult keratinocytes. Under the conditions used, normal cells established functional communication channels with each cell line tested, showing no selectivity. These results suggest that progressive loss of homologous but not heterologous IC capacity accompanies neoplastic development in mouse skin carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1994

Decreased connexin expression and intercellular communication in human bladder cancer cells.

Connexins make up a gene family encoding proteins that form intercellular channels known as gap junctions. Decreases in connexin expression and loss of intercellular communication have been associated with the malignant phenotype in some animal and human cells. The expression of connexin 26 and 43 mRNA was evaluated in cultured normal and malignant human urothelial cells. The normal urothelial cells were shown by Northern analysis to express both connexins. Increased confluence of the cultured normal human urothelial cells was associated with upregulation of connexin 26 mRNA. Connexin 26 mRNA expression was decreased in the bladder cancer cells. Using a human connexin 26 complementary DNA probe, nuclear run-on assays demonstrated that the decreased expression in the cancer cells was due to a failure of transcription. Southern blot analysis did not reveal any alterations in the genomic DNA. Assessment of gap junction function by scrape loading of lucifer yellow demonstrated dye transfer in normal urothelial cells but not in bladder cancer cells. Downregulation of connexin 26 mRNA was associated with functional loss of intercellular communication in the human bladder cancer cells. Connexin 43 expression varied considerably in the bladder cancer cell lines and did not correlate with dye transfer of lucifer yellow. These data suggest that alterations in the regulation of connexin 26 expression are associated with and may contribute to the malignant phenotype in bladder cancer.

Cell Communication↗
PubMed2006

Effect of thioridazine on gap junction intercellular communication in connexin 43-expressing cells.

Propagation of electrical activity between myocytes in the heart requires gap junction channels, which contribute to coordinated conduction of the heartbeat. Some antipsychotic drugs, such as thioridazine and its active metabolite, mesoridazine, have known cardiac conduction side-effects, which have resulted in fatal or nearly fatal clinical consequences in patients. The physiological mechanisms responsible for these cardiac side-effects are unknown. We tested the effect of thioridazine and mesoridazine on gap junction-mediated intercellular communication between cells that express the major cardiac gap junction subtype connexin 43. Micromolar concentrations of thioridazine and mesoridazine inhibited gap junction-mediated intercellular communication between WB-F344 epithelial cells in a dose-dependent manner, as measured by fluorescent dye transfer. Kinetic analyses demonstrated that inhibition by 10 micromol/L thioridazine occurred within 5 min, achieved its maximal effect within 1 h, and was maintained for at least 24 h. Inhibition was reversible within 1 h upon removal of the drug. Western blot analysis of connexin 43 in a membrane-enriched fraction of WB-F344 cells treated with thioridazine revealed decreased amounts of unphosphorylated connexin 43, and appearance of a phosphorylated connexin 43 band that co-migrated with a "hyperphosphorylated" connexin 43 band present in TPA-inhibited cells. When tested for its effects on cardiomyocytes isolated from neonatal rats, thioridazine decreased fluorescent dye transfer between colonies of beating myocytes. Microinjection of individual cells with fluorescent dye also showed inhibition of dye transfer in thioridazine-treated cells compared to vehicle-treated cells. In addition, thioridazine, like TPA, inhibited rhythmic beating of myocytes within 15 min of application. In light of the fact that the thioridazine and mesoridazine concentrations used in these experiments are in the range of those used clinically in patients, our results suggest that inhibition of gap junction intercellular communication may be one factor contributing to the cardiac side-effects observed in some patients taking these medications.

Animals↗
PubMed1997

Loss of gap junction plaques and inhibition of intercellular communication in ilimaquinone-treated BICR-M1Rk and NRK cells.

To examine the mechanism(s) and pathways of gap junction formation and removal a novel and reversible inhibitor of protein secretion, ilimaquinone (IQ), was employed. IQ has been reported to cause the vesiculation of Golgi membranes, block protein transport at the cis-Golgi and depolymerize cytoplasmic microtubules. Connexin43 (Cx43) immunolabeling and dye microinjection experiments revealed that gap junction plaques were lost and intercellular communication was inhibited following IQ treatment for 1 hr in BICR-M1Rk rat mammary tumor cells and for 2 hr in normal rat kidney (NRK) cells. Gap junction plaques and intercellular communication recovered within 2 hr when IQ was removed. IQ, however, did not affect the distribution of zonula occludens-1, a protein associated with tight junctions. Western blot analysis revealed that the IQ-induced loss of gap junction plaques was accompanied by a limited reduction in the highly phosphorylated form of Cx43, previously shown to be correlated with gap junction plaques. The presence of IQ inhibited the formation of new gap junction plaques in BICR-M1Rk cells under conditions where preexisting gap junctions were downregulated by brefeldin A treatment. Treatment of BICR-M1Rk and NRK cells with other microtubule depolymerization agents did not inhibit plaque formation or promote rapid gap junction removal. These findings suggest that IQ disrupts intercellular communication by inhibiting the events that are involved in plaque formation and/or retention at the cell surface independent of its effects on microtubules. Our results also suggest that additional factors other than phosphorylation are necessary for Cx43 assembly into gap junction plaques.

Animals↗
PubMed1990

Ultrastructural differences in junctional intercellular communication between highly and weakly metastatic clones derived from rat mammary carcinoma.

We examined by electron microscopy the differences in junctional intercellular communications among highly metastatic clones, weakly metastatic clones, and the parent clone obtained from a spontaneously developed rat mammary carcinoma. We also investigated intercellular communications of the highly and weakly metastatic clone cells with normal fibroblasts. The results showed that ultrastructural changes of the highly metastatic clone cells, such as microvilli, microfilaments, and small organelles including endoplasmic reticulum, Golgi apparatus, and mucous particles, were more distinct than those of the weakly metastatic clone cells, and that the numbers of desmosome and gap junctions of weakly metastatic clone cells were significantly greater than those of highly metastatic clone cells. The formation of gap junctions and desmosomes was found only between weakly metastatic clone cells and normal fibroblasts. When both highly and weakly metastatic clone cells were cultured with normal fibroblasts, a tight junction was observed only in the culture of weakly metastatic clone cells and normal fibroblasts. These results suggest that ultrastructural differences are related to the proliferation and detachment of tumor cells from the primary site in the initial stage of tumor metastasis.

Animals↗
PubMed1989

Synergistic inhibition of metabolic cooperation by oleic acid or 12-0-tetradecanoylphorbol-13-acetate and dichlorodiphenyltrichlorethane (DDT) in Chinese hamster V79 cells: implication of a role for protein kinase C in the regulation of gap junctional intercellular communication.

The effects of TPA and/or DDT and oleic acid and/or DDT on gap junction-mediated intercellular communication (i.e. metabolic cooperation) between Chinese hamster V79 cells was examined. Addition of TPA, DDT or oleic acid alone to cocultures of 6-thioguanine-resistant (6-TGR) and 6-thioguanine-sensitive (6-TGS) V79 cells significantly increased the recovery of 6-TGR cells indicating inhibition of metabolic cooperation. In the presence of TPA and DDT or oleic acid and DDT the observed recovery of 6-TGR cells was significantly greater than the expected (calculated) additive 6-TGR cell recovery. No synergistic increases in 6-TGR cell recovery were observed when co-cultures of V79 cells were exposed to dieldrin and DDT. These results indicate that TPA and DDT or oleic acid and DDT can act synergistically to inhibit metabolic cooperation. These data suggest a role for protein kinase C in the regulation of gap junction-mediated intercellular communication.

Animals↗
PubMed1990

Chemical, oncogene and growth factor inhibition gap junctional intercellular communication: an integrative hypothesis of carcinogenesis.

Most, if not all, cancer cells have some dysfunction in gap-junction-mediated intercellular communication, either because of defects in cell adhesion or inability to have functional gap junctional communication. In addition, most, if not all, tumor-promoting chemicals and conditions down-regulate gap junction function, while some antitumor-promoting chemicals can up-regulate gap junctional communication. Several oncogenes are associated with down-regulation of gap junction function and several hormone and growth regulators, known to be tumor promoters, are also able to down-regulate gap junction function. On the other hand, some tumor suppressor genes have been linked to the up-regulation of gap junctions. Based on these observations, it is hypothesized that, if a progenitor cell is unable to perform gap junctional intercellular communication, normal growth control and cell differentiation would not be possible, thereby favoring the development of malignant neoplasia.

Animals↗
PubMed1989

Volatile anesthetics block intercellular communication between neonatal rat myocardial cells.

The effects of halothane and ethrane on gap junction-mediated intercellular communication and on membrane excitability were examined in cultured neonatal rat cardiac myocytes using whole-cell voltage-clamp and current-clamp techniques. Excitability was maintained at doses of both anesthetics that reversibly abolished current flow through junctional membranes. The degree of reduction of junctional conductance was a steep function of the dose of anesthetic; complete block occurred at lower aqueous concentrations of halothane than ethrane. The time course for loss of communication was rapid; 90% reduction of initial junctional conductance occurred in less than 15 seconds after exposure to 2 mM halothane or 4 mM ethrane. Recovery of junctional conductance and junctional permeability to intracellularly injected Lucifer yellow was rapid and complete on washout of the anesthetics. As junctional conductance was reduced by halothane or ethrane exposure, unitary conductance of the gap junctional channels remained constant at about 50 pS. Uncoupling by these anesthetics is thus attributable to a decrease in the number of conducting channels rather than to reduction of the channel's unitary conductance. The data are discussed with regard to the possible role of this intercellular communication pathway in the arrhythmias and alterations of conduction velocity and contractility produced by volatile anesthetics.

Animals↗