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PubMed2004

Paracrine effect of TGF-beta1 on downregulation of gap junctional intercellular communication between human dermal fibroblasts.

Disruption of gap junctional intercellular communication (GJIC) is associated with tumor progression during multistage carcinogenesis. A coordinated interaction of epithelial tumor cells with the stromal environment via growth factors is a prerequisite for tumor invasion. Here, the involvement of growth factors in downregulation of homologous GJIC of dermal fibroblasts, used as model for stromal cells, was examined. Tumor cell derived transforming growth factor-beta1 (TGF-beta1), having oncogenic activities at late stages of carcinogenesis, was identified as being responsible for downregulation of GJIC via an increase in the level of reactive oxygen species in stromal fibroblasts. Lowering the level of reactive oxygen species by antioxidants, such as the cell-permeable N-acetyl-L-cysteine, prevented TGF-beta1-mediated downregulation of intercellular communication between confluent fibroblasts.

Cell Communication↗
PubMed1994

Increased gap junctional intercellular communication capacity and connexin 43 and 26 expression in rat bladder carcinogenesis.

Many reports have suggested that gap junctional intercellular communication or gap junction proteins (connexins) could have tumor suppression characteristics. We investigated gap junctional intercellular communication capacity and connexin 26, 32 and 43 mRNA expression in four rat bladder cell lines and the results were compared to their tumorigenicity. We also examined connexin expression in rat bladder carcinomas induced by 3,2'-dimethyl-4-aminobiphenyl or N-ethyl-N-(4-hydroxybutyl)nitrosamine (EHBN) and in normal bladders. There was clear tendency that cell lines with greater communication had stronger tumorigenicity and more expression of connexin 26 or 43. We could not detect connexin 32 in these cell lines. In normal bladder tissue, connexin 43 expression was barely detectable and there was no detectable connexin 26. However, in rat bladder carcinomas, especially the EHBN-induced carcinomas, abundant expression of both connexins was observed. These results indicate that increased gap junctional intercellular communication capacity or increased connexin(s) expression may give a growth advantage in rat bladder carcinogenesis.

Aminobiphenyl Compounds↗
PubMed2003

The role of stem cells and gap junctional intercellular communication in carcinogenesis.

Understanding the process of carcinogenesis will involve both the accumulation of many scientific facts derived from molecular, biochemical, cellular, physiological, whole animal experiments and epidemiological studies, as well as from conceptual understanding as to how to order and integrate those facts. From decades of cancer research, a number of the "hallmarks of cancer" have been identified, as well as their attendant concepts, including oncogenes, tumor suppressor genes, cell cycle biochemistry, hypotheses of metastasis, angiogenesis, etc. While all these "hallmarks" are well known, two important concepts, with their associated scientific observations, have been generally ignored by many in the cancer research field. The objective of the short review is to highlight the concept of the role of human adult pluri-potent stem cells as "target cells" for the carcinogenic process and the concept of the role of gap junctional intercellular communication in the multi-stage, multi-mechanism process of carcinogenesis. With these two concepts, an attempt has been made to integrate the other well-known concepts, such as the multi-stage, multimechanisn or the "initiation/promotion/progression" hypothesis; the stem cell theory of carcinogenesis; the oncogene/tumor suppression theory and the mutation/epigenetic theories of carcinogenesis. This new "integrative" theory tries to explain the well-known "hallmarks" of cancers, including the observation that cancer cells lack either heterologous or homologous gap junctional intercellular communication whereas normal human adult stem cells do not have expressed or functional gap junctional intercellular communication. On the other hand, their normal differentiated, non-stem cell derivatives do express connexins and express gap junctional intercellular communication during their differentiation. Examination of the roles of chemical tumor promoters, oncogenes, connexin knock-out mice and roles of genetically-engineered tumor and normal cells with connexin and anti-sense connexin genes, respectively, seems to provide evidence which is consistent with the roles of both stem cells and gap junctional communication playing a major role in carcinogenesis. The integrative hypothesis provides new strategies for chemoprevention and chemotherapy which focuses on modulating connexin gene expression or gap junctional intercellular communication in the premalignant and malignant cells, respectively.

Cell Communication↗
PubMed1991

Contact-dependent intercellular communication of bovine luteal cells in culture.

Mammalian gap junctions permit exchange of nutrients, ions, and regulatory molecules of less than 1.5 kDa among contacting communication-competent cells and may be important for regulation of luteal function and maintenance of luteal homeostasis. The present studies were designed to evaluate gap junction-mediated intercellular communication between bovine luteal cells in culture. Using a dye-coupling technique along with interactive laser cytometry, selected luteal cells were studied for the rate of contact-dependent fluorescence redistribution after photobleaching. The rate of communication, reported as the rate of fluorescence recovery (percentage per min), was determined for steroidogenic cells as follows: 1) small luteal cells contacting only small luteal cells, 2) large luteal cells contacting only small luteal cells, and 3) large luteal cells contacting only large luteal cells. In addition, the effects of known regulators of luteal function [LH, prostaglandin F2 alpha (PGF), and forskolin] on the rate of intercellular communication were determined. Small luteal cells communicated rapidly with each other, exhibiting an initial rate of fluorescence recovery of 4.1 +/- 0.1%/min (n = 187). The rate of small cell-small cell communication was unaffected by LH and PGF. For large luteal cells contacting small luteal cells, however, LH and PGF stimulated (P less than 0.02) the rate of communication compared with no hormone [1.6 +/- 0.2 (n = 18) and 1.5 +/- 0.6 (n = 20) vs. 0.8 +/- 0.3%/min (n = 27), respectively]. LH and PGF in combination, however, did not enhance the rate (0.6 +/- 0.2%/min; n = 19) of large cell-small cell communication. In contrast, forskolin significantly stimulated both small cell-small cell and large cell-small cell communication rates compared with no forskolin [34% increase (n = 48) and 50% increase (n = 23), respectively]. Large luteal cells did not communicate with each other under any condition tested. Transmission electron microscopy revealed the presence of numerous gap junction-like structures in bovine luteal cells in culture. These data suggest that luteal cells are capable of intercellular communication and that the rate of communication may be influenced by hormones. Contact-dependent intercellular communication among luteal cells may, therefore, play a significant role in the regulation of luteal function.

Animals↗
PubMed1986

Inhibition of gap junctional intercellular communication in human teratocarcinoma cells by organochlorine pesticides.

Inhibition of intercellular communication, as measured by metabolic cooperation between 6-thioguanine-sensitive and 6-thioguanine-resistant Chinese hamster V79 cells, has been previously shown to be correlated with a large variety of known tumor promoters, including some of the organochlorine pesticides. Since further evidence concerning the effects of those known or suspected animal tumor promoters on human cells is needed, three organochlorine pesticides, dieldrin, aldrin, and 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), were tested for their ability to inhibit metabolic cooperation between 6-thioguanine-sensitive (6TGs, HTP3-4) and 6-thioguanine-resistant (6TGr, HTXTG-1) human teratocarcinoma cells. Similar to the effect of the known mouse skin tumor promoter 12-tetradecanoyl phorbol-13-acetate (TPA), all three pesticides inhibited gap junctional intercellular communication within a noncytotoxic dose range. The dose-response curves of these chemicals were similar to those of other known tumor promoters on Chinese hamster V79 cells. In addition, the transfer of [3H]uridine between teratocarcinoma cells in contact was reduced after pesticide treatment.

Aldrin↗
PubMed1992

Reversible inhibition of intercellular communication among cardiac myocytes by halogenated hydrocarbons.

We examined the effect of 11 aliphatic halogenated hydrocarbons on the transfer of microinjected dye among cardiac myocytes from neonatal rats. Myocytes were suffused with increasing concentrations of halocarbon added as a 0.2% solution of dimethyl sulfoxide to M199 containing 1.8 mM Ca and 5% serum. Single cells were microinjected with the fluorescent probe Lucifer yellow (5% in 0.1 mM LiCl) and dye coupling to adjacent cells was monitored. All of the halocarbons tested exhibited a concentration-dependent inhibitory effect on intercellular communication that was reversible following washout of the compounds. Intercellular communication was blocked within 1 min of exposure to an effective concentration, and recovery of communication occurred even after 2 hr of exposure. Pretreatment of cells with SKF 525-A (25 microM) did not prevent the inhibition of intercellular communication by carbon tetrachloride suggesting an absence of P-450 involvement. EC50s were calculated for each chemical using probit analysis. A log-log comparison of the EC50s and the physicochemical properties of the chemicals demonstrated a high correlation (R2 = 0.933) between the EC50s and the octanol/water partition coefficients of the halocarbons. This suggests that incorporation of halocarbons in the membrane may block intercellular communication through modification of the immediate environment of the gap junctions. The results are in agreement with the hypothesis that inhibition of gap junctional communication is a factor in the arrhythmogenic effects of acute halocarbon exposure.

Animals↗
PubMed1997

[Effects of diesel exhaust particle on gap junction intercellular communication].

Scrape-loading and dye transfer technique (SLDT) was used to study the effects of diesel exhaust particle (DEP) on gap junction intercellular communication (GJIC). The results demonstrated that the extract of DEP caused inhibition of gap junction intercellular communication in Balb/c 3T3 cells. It was suggested that inhibition of gap junction intercellular communication in cells may be one of the cause to induce cell transformation.

3T3 Cells↗
PubMed1991

Inhibition of intercellular communication in Chinese hamster V79 cells by fractionated asphalt fume condensates.

Asphalt fume condensate is a skin carcinogen in mice, yet this complex mixture contains relatively low levels of known carcinogenic initiators. Consequently, its biological activity has been attributed to the presence of cocarcinogenic or tumor-promoting agents. One of several proposed mechanisms of tumor promotion is inhibition of intercellular communication. In an attempt to determine if asphalt fume has tumor-promoting potential inhibition of intercellular communication was measured in V79 cells exposed to fractionated asphalt fume condensate. Fume from air-blown Arabian crude asphalt was trapped and separated into five fractions by preparative-scale high-pressure liquid chromatography. The parent fume condensate and the five fractions inhibited intercellular communication in a concentration-dependent fashion, with a minimum effective concentration of 2.5 microgram/ml for the most potent fraction. Cytotoxicity assays were performed at the same time and concentrations as the metabolic cooperation assays. Cytotoxic responses paralleled the inhibition of intercellular communication.

Aerosols↗
PubMed1994

Cell culture assays for chemicals with tumor-promoting or tumor-inhibiting activity based on the modulation of intercellular communication.

The ability of chemicals with tumor-promoting or tumor-inhibiting activity to modulate gap junctional intercellular communication is reviewed. The two most extensively used types of assays for screening tests are (1) metabolic cooperation assays involving exchange between cells of precursors of nucleic acid synthesis and (2) dye-transfer assays that measure exchange of fluorescent dye from loaded cells to adjacent cells. About 300 substances of different biological activities have been studied using various assays. For tumor promoters/epigenetic carcinogens, metabolic cooperation assays have a sensitivity of 62% and dye-transfer assays 60%. Thirty percent of DNA-reactive carcinogens also possess the ability to uncouple cells. The complete estimation of the predictive power of these assays could not be made because the majority of the substances studied for intercellular communication effects in vitro have not yet been studied for promoting activity in vivo. Both metabolic cooperation assays and dye transfer assays respond well to the following classes of substances: phorbol esters, organochlorine pesticides, polybrominated biphenyls, promoters for urinary bladder, some biological toxins, peroxisome proliferators, and some complex mixtures. Results of in vitro assays for such tumor promoters/nongenotoxic carcinogens, such as some bile acids, some peroxides, alkanes, some hormones, mineral dusts, ascorbic acid, okadaic acid, and benz(e)pyrene, do not correlate with the data of in vivo two-stage or complete carcinogenesis. Enhancement of intercellular communication was found for 18 chemicals. Among these, cAMP, retinoids, and carotenoids have demonstrated inhibition of carcinogenesis. We examine a number of factors that are important for routine screening, including the requirement for biotransformation for some agents to exert effects on gap junctions. We also discuss the mechanisms of tumor promoter and tumor inhibitor effects on gap junctional permeability, including influences of protein kinase activation, changes in proton and Ca2+ intracellular concentrations, and effects of oxy radical production.

Animals↗
PubMed1994

Gap junctional intercellular communication of cultured rat liver parenchymal cells is stabilized by epithelial cells and their isolated plasma membranes.

The gap junctional intercellular communication (GJIC) determined by measuring dye coupling with Lucifer yellow, decreased within 3 d from 66% to 28% in monocultures of rat liver parenchymal cells. Coculturing of the parenchymal cells with a nonparenchymal epithelial cell line from rat liver resulted in increased and stabilized intercellular communication (83% after 3 d). The presence of isolated plasma membrane vesicles of the nonparenchymal epithelial cells also stabilized the intercellular communication between the liver parenchymal cells (70% after 3 d). When liver parenchymal cells were cocultured with a rat liver fibroblast cell line the gap junctional communication between the parenchymal cells was not stabilized (43% after 3 d), and isolated plasma membrane vesicles of the fibroblast were also unable to support the GJIC in parenchymal cells (35% after 3 d). It is concluded that plasma membrane constituents of the nonparenchymal epithelial cells were responsible for the stabilization of the GJIC between parenchymal cells. A heterotypic gap junctional communication between parenchymal and nonparenchymal cells was not observed.

Animals↗
PubMed1989

Mechanistic studies on the DDT-induced inhibition of intercellular communication.

Two structurally unrelated compounds, 1,1'-(2,2,2-trichloroethylidene) bis(4-chlorobenzene) (DDT) and 12-O-tetradecanoylphorbol-13-acetate (TPA), are both potent inhibitors of cell-cell communication in vitro as well as tumour promoters in vivo. There is evidence that TPA acts via a specific receptor mechanism involving activation of protein kinase C (pkC). The mechanism of action of DDT has been discussed in terms of membrane perturbation, increased intracellular calcium, interaction with calmodulin and decreased cAMP levels. In the present study the objective was to examine the potential role of pkC activation in DDT-induced inhibition of intercellular communication in cultured cells. The V79 metabolic cooperation assay was used for measuring intercellular communication. Furthermore, the effects of DDT on the activity of partially purified pkC from V79 cells was measured, as was the interaction of DDT with the phorbol ester/DAG-binding site on the pkC enzyme. Results from the biochemical studies showed that DDT neither activates pkC nor binds to the phorbol ester/DAG-binding site, as measured by displacement of PDBU binding. Using the metabolic cooperation assay it was demonstrated that pretreatment with TPA made cells refractory, i.e. a second application of TPA did not inhibit cell-cell communication. DDT added to cells down-regulated with TPA inhibited cell-cell communication, even though these cells were refractive to TPA. This result further supports the hypothesis that DDT and TPA inhibit intercellular communication primarily by different pathways. At non-cytotoxic concentrations, pkC inhibitors (H7, W7 and palmitoyl carnitine) did not affect the TPA- or DDT-induced inhibition of cell-cell communication in the V79 metabolic cooperation assay. Quercetin, a pkC inhibitor which has been reported to eliminate DDT- or TPA-induced inhibition of intercellular communication, was investigated in an in vivo study that measured promotion of enzyme-altered foci in DEN-treated rat liver. Quercetin co-administered with DDT did not act as an antipromoter.

Animals↗
PubMed2005

Astaxanthin diminishes gap junctional intercellular communication in primary human fibroblasts.

Astaxanthin is a carotenoid found in plants and algae; it provides the color of marine seafood such as salmon, lobster, or shrimp. Carotenoids are antioxidants and exhibit other biological functions, including effects on gap junctional communication important for homeostasis, growth control, and development of cells. Cancer cells have an impaired gap junctional intercellular communication. The objective of the present study was to determine the effects of astaxanthin and canthaxanthin on gap junctional intercellular communication in vitro. Primary human skin fibroblasts were exposed to carotenoids from 0.001 to 10 micromol/L, and gap junctional communication was measured with a dye transfer assay. After incubation with canthaxanthin for 24 and 72 h, intercellular communication increased, whereas it was strongly diminished by astaxanthin at levels > 0.1 micromol/L. Inhibition was reversed when astaxanthin was withdrawn. Western blot analysis showed that after exposure to canthaxanthin, the amount of the gap junction protein connexin43 was increased. Incubation with astaxanthin led to a change in the phosphorylation pattern of connexin43, shifting from higher to lower phosphorylation states. We suggest that astaxanthin affects channel function by changing the phosphorylation pattern of connexin43.

Anticarcinogenic Agents↗
PubMed1990

[Role of junctional intercellular communication in hepatic carcinogenesis in rats].

Two major alterations in gap junctional intercellular communication (GJIC) during experimental carcinogenesis have been seen: a decrease of its capacity during tumor promotion and a selective loss of intercellular communication between transformed cells and surrounding normal counterparts. These data, first discovered in our laboratory on mouse fibroblasts (BALB/c 3T3), were partly confirmed in rat liver epithelial cells. In such cells, the decreased GJIC was related to their level of transformation. Tissue-specific effect of tumor promoters is also seen in the inhibition of GJIC; administration of phenobarbital decreased the level of GJ mRNA in the liver, but not in other organs tested. Phenobarbital also inhibited GJIC among adult rat hepatocytes co-cultured with BALB/c 3T3 cells but not among the mouse fibroblasts. Moreover, our findings on the diminished level of GJ mRNA in tumors of rat liver support the importance of acquired selective GJIC in rat liver carcinogenesis.

Animals↗
PubMed1993

Intercellular communication within the rat anterior pituitary gland: V. Changes in cell-to-cell communications as a function of the timing of castration in male rats.

Cell-to-cell communication by gap junctions was investigated in the male rat anterior pituitary gland following several experimental regimens involving castration. The regimens included the following animals: (1) Group 1, castrated at 10-day intervals from day 10 to 50 and sacrificed at 60 days of age; (2) Group 2, castrated every 10 days from days 10 to 50 and sacrificed 50 days after castration; (3) Group 3, castrated at 5 days of age and sacrificed every 10 days from day 10 to 60; or (4) Group 4, remained intact and sacrificed every 10 days from days 10 to 60. In all of the castrated animals, numerous so-called castration cells were scattered throughout the pars distalis of the pituitary gland, with occasional "signet ring cells" being observed. In Groups 1 and 2, the pattern of gap junction development and their number was no different from the intact control (Group 4). In contrast, the number of gap junctions in the animals castrated on day 5 remained very small even into adulthood. These data demonstrate that gonadal steroids are important in the initial development of gap junctions within the pituitary gland but are not necessary to sustain their presence once an animal becomes an adult.

Animals↗
PubMed1992

Similarities between legume-rhizobium communication and steroid-mediated intercellular communication in vertebrates.

Regulation of the actions of flavonoids and Nod factors in legume-rhizobia communication has several interesting similarities with that of steroid-mediated actions in vertebrates. Oxidation or reduction of flavonoids and Nod factors modifies their biological activity just as, for example, oxidation of an alcohol at C11 on hydrocortisone regulates its biological activity. Second, some flavonoids are anti-inducers, functioning like steroid antagonists to negate the actions of inducer flavonoids. Amino acid sequence analyses show that human 17 beta-hydroxysteroid dehydrogenase, which catalyzes the interconversion of the alcohol and ketone at C17 on estrogens and androgens, and rat 11 beta-hydroxysteroid dehydrogenase, which catalyzes the interconversion of the alcohol and ketone at C11 of glucocorticoids, and Rhizobium meliloti NodG and Bradyrhizobium japonicum. FixR are derived from a common ancestor. Just as steroid-metabolizing enzymes can regulate steroid-mediated gene transcription, enzymes that modify substituents on flavonoids and Nod factors may have a similar role in regulating signalling between legumes and rhizobia. The enzymes that modify flavonoids and Nod factors have not yet been identified. However, NodG and FixR are two likely candidates to have this role in regulating legume-rhizobia signalling.

Amino Acid Sequence↗
PubMed1989

Prevention of cytotoxicity and inhibition of intercellular communication by antioxidant catechins isolated from Chinese green tea.

An antioxidant fraction of Chinese green tea (green tea antioxidant; GTA), containing several catechins, has been previously shown to inhibit 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced tumor promotion in mouse skin. In the present study, GTA was shown to have antioxidative activity toward hydrogen peroxide (H2O2) and the superoxide radical (O2-). GTA also prevented oxygen radical and H2O2-induced cytotoxicity and inhibition of intercellular communication in cultured B6C3F1 mouse hepatocytes and human keratinocytes (NHEK cells). GTA (0.05-50 micrograms/ml) prevented the killing of hepatocytes (measured by lactate dehydrogenase release) by paraquat (1-10 mM) and glucose oxidase (0.8-40 micrograms/ml) in a concentration-dependent fashion. GTA (50 micrograms/ml) also prevented the inhibition of hepatocyte intercellular communication by paraquat (5 mM), glucose oxidase (0.8 micrograms/ml), and phenobarbital (500 micrograms/ml). In addition, GTA (50 micrograms/ml) prevented the inhibition of intercellular communication in human keratinocytes by TPA (100 ng/ml). Cytotoxicity and inhibition of intercellular communication, two possible mechanisms by which tumor promoters may produce their promoting effects were therefore prevented by GTA. The inhibition of these two effects of pro-oxidant compounds may suggest a mechanism by which GTA inhibits tumor promotion in vivo.

Animals↗