scholarly journals A bioelectric model of carcinogenesis, including propagation of cell membrane depolarization and reversal therapies

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Joao Carvalho
Keyword(s):  
Cell Membrane ◽  
Gap Junctions ◽  
Polarization State ◽  
Cell Communication ◽  
Ionic Exchange ◽  
Cellular Origin ◽  
Tissue Organization ◽  
Tissue Organization Field Theory ◽  
Cell Depolarization ◽  
A Chain

AbstractAs the main theory of carcinogenesis, the Somatic Mutation Theory, increasingly presents difficulties to explain some experimental observations, different theories are being proposed. A major alternative approach is the Tissue Organization Field Theory, which explains cancer origin as a tissue regulation disease instead of having a mainly cellular origin. This work fits in the latter hypothesis, proposing the bioelectric field, in particular the cell membrane polarization state, and ionic exchange through ion channels and gap junctions, as an important mechanism of cell communication and tissue organization and regulation. Taking into account recent experimental results and proposed bioelectric models, a computational model of cancer initiation was developed, including the propagation of a cell depolarization wave in the tissue under consideration. Cell depolarization leads to a change in its state, with the activation and deactivation of several regulation pathways, increasing cell proliferation and motility, changing its epigenetic state to a more stem cell-like behavior without the requirement of genomic mutation. The intercellular communication via gap junctions leads, in certain circumstances, to a bioelectric state propagation to neighbor cells, in a chain-like reaction, till an electric discontinuity is reached. However, this is a reversible process, and it was shown experimentally that, by implementing a therapy targeted on cell ion exchange channels, it is possible to reverse the state and repolarize cells. This mechanism can be an important alternative way in cancer prevention, diagnosis and therapy, and new experiments are proposed to test the presented hypothesis.

scholarly journals A Bioelectric Model of Carcinogenesis, Including Propagation of Cell Membrane Depolarization and Reversal Therapies

2021 ◽  
Author(s):  
Joao Carvalho
Keyword(s):  
Cell Membrane ◽  
Gap Junctions ◽  
Polarization State ◽  
Cell Communication ◽  
Ionic Exchange ◽  
Cellular Origin ◽  
Tissue Organization ◽  
Tissue Organization Field Theory ◽  
Cell Depolarization ◽  
A Chain

Abstract As the main theory of carcinogenesis, the Somatic Mutation Theory, increasingly presents difficulties to explain some experimental observations, different theories are being proposed. A major alternative approach is the Tissue Organization Field Theory, which explains cancer origin as a tissue regulation disease instead of having a mainly cellular origin. This work fits in the latter hypothesis, proposing the bioelectric field, in particular the cell membrane polarization state, and ionic exchange through ion channels and gap junctions, as an important mechanism of cell communication and tissue organization and regulation. Taking into account recent experimental results and proposed bioelectric models, a computational model of cancer initiation was developed, including the propagation of a cell depolarization wave in the tissue under consideration. Cell depolarization leads to a change in its state, with the activation and deactivation of several regulation pathways, increasing cell proliferation and motility, changing its epigenetic state to a more stem cell-like behavior without the requirement of genomic mutation. The intercellular communication via gap junctions leads, in certain circum stances, to a bioelectric state propagation to neighbor cells, in a chain-like reaction, till an electric discontinuity is reached. However, this is a reversible process, and it was shown experimentally that, by implementing a therapy targeted on cell ion exchange channels, it is possible to reverse the state and repolarize cells. This mechanism can be an important alternative way in cancer prevention, diagnosis and therapy, and new experiments are proposed to test the presented hypothesis.

scholarly journals Heteromerization of Innexin Gap Junction Proteins Regulates Epithelial Tissue Organization in Drosophila

2006 ◽  
Vol 17 (4) ◽  
pp. 1676-1685 ◽  
Author(s):  
Corinna Lehmann ◽  
Hildegard Lechner ◽  
Birgit Löer ◽  
Martin Knieps ◽  
Sonja Herrmann ◽  
...  
Keyword(s):  
Gap Junctions ◽  
Gap Junction ◽  
Ectopic Expression ◽  
Cell Communication ◽  
Epithelial Tissue ◽  
Surface Plasmon Resonance Analysis ◽  
Gap Junction Channels ◽  
Tissue Organization ◽  
Biochemical Fractionation

Gap junctions consist of clusters of intercellular channels, which enable direct cell-to-cell communication and adhesion in animals. Whereas deuterostomes, including all vertebrates, use members of the connexin and pannexin multiprotein families to assemble gap junction channels, protostomes such as Drosophila and Caenorhabditis elegans use members of the innexin protein family. The molecular composition of innexin-containing gap junctions and the functional significance of innexin oligomerization for development are largely unknown. Here, we report that heteromerization of Drosophila innexins 2 and 3 is crucial for epithelial organization and polarity of the embryonic epidermis. Both innexins colocalize in epithelial cell membranes. Innexin3 is mislocalized to the cytoplasm in innexin2 mutants and is recruited into ectopic expression domains defined by innexin2 misexpression. Conversely, RNA interference (RNAi) knockdown of innexin3 causes mislocalization of innexin2 and of DE-cadherin, causing cell polarity defects in the epidermis. Biochemical interaction studies, surface plasmon resonance analysis, transgenesis, and biochemical fractionation experiments demonstrate that both innexins interact via their C-terminal cytoplasmic domains during the assembly of heteromeric channels. Our data provide the first molecular and functional demonstration that innexin heteromerization occurs in vivo and reveal insight into a molecular mechanism by which innexins may oligomerize into heteromeric gap junction channels.

scholarly journals Effects of Alpha-Connexin Carboxyl-Terminal Peptide (aCT1) and Bowman-Birk Protease Inhibitor (BBI) on Canine Oral Mucosal Melanoma (OMM) Cells

2021 ◽  
Vol 8 ◽  
Author(s):  
Ayami Sato ◽  
Ivone Izabel Mackowiak da Fonseca ◽  
Márcia Kazumi Nagamine ◽  
Gabriela Fernandes de Toledo ◽  
Rennan Olio ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Protease Inhibitor ◽  
Gap Junctions ◽  
Cell Viability ◽  
Cancer Cells ◽  
Cell Communication ◽  
Cx43 Expression ◽  
Altered Expression ◽  
Junction Protein ◽  
Carboxyl Terminal

Oral mucosal melanomas (OMM) are aggressive cancers in dogs, and are good models for human OMM. Gap junctions are composed of connexin units, which may have altered expression patterns and/or subcellular localization in cancer cells. Cell-to-cell communication by gap junctions is often impaired in cancer cells, including in melanomas. Meanwhile, the upregulated expression of the gap junction protein connexin 43 (Cx43) inhibits melanoma progression. The α-connexin carboxyl-terminal (aCT1) peptide reportedly maintains Cx43 expression and cell-cell communication in human mammary cells and increases the communication activity through gap junctions in functional assays, therefore causing decreased cell proliferation. The Bowman-Birk protease inhibitor (BBI), a component of soybeans, induces Cx43 expression in several tumor cells as a trypsin–chymotrypsin inhibition function, with antineoplastic effects. This study investigated the effect of aCT1 peptide and BBI treatment, alone or in combination, on TLM1 canine melanoma cell viability. Cell viability after treatment with aCT1, the reverse sequence peptide (R-pep), and/or BBI for 5 days was analyzed by PrestoBlue assay. Immunofluorescence was used to observe Cx43 localization and expression. aCT1 (200 μM) alone did not significantly decrease cell viability in TLM1 cells, whereas BBI (400 μg/ml) alone significantly decreased the TLM1 viability. Combined treatment with both aCT1 (200 μM) and BBI (400 μg/ml) significantly decreased cell viability in TLM1 cells. Cx43 expression, as identified by immunostainings in TLM1 cells, was increased in the cell membrane after the combination treatment with BBI and aCT1. This dual treatment can be combined to achieve the anticancer activity, possibly by increasing Cx 43 expression and affecting Cx43 migration to the cell membrane. In conclusion, a treatment strategy targeting Cx43 with BBI and aCT1 may possibly lead to new effective therapies for canine OMM.

Gap junctions in the prothoracic glands of the tobacco hornworm, Manduca sexta

1992 ◽  
Vol 50 (1) ◽  
pp. 706-707
Author(s):  
Ji-da Dai ◽  
M. Joseph Costello ◽  
Lawrence I. Gilbert
Keyword(s):  
Gap Junctions ◽  
Small Molecules ◽  
Manduca Sexta ◽  
Freeze Fracture ◽  
Cell Communication ◽  
Cellular Level ◽  
Thin Sections ◽  
Prothoracic Glands ◽  
Polyhydroxylated Steroids ◽  
Stimulation Of

Insect molting and metamorphosis are elicited by a class of polyhydroxylated steroids, ecdysteroids, that originate in the prothoracic glands (PGs). Prothoracicotropic hormone stimulation of steroidogenesis by the PGs at the cellular level involves both calcium and cAMP. Cell-to-cell communication mediated by gap junctions may play a key role in regulating signal transduction by controlling the transmission of small molecules and ions between adjacent cells. This is the first report of gap junctions in the PGs, the evidence obtained by means of SEM, thin sections and freeze-fracture replicas.

scholarly journals A Cellular Assay for the Identification and Characterization of Connexin Gap Junction Modulators

2021 ◽  
Vol 22 (3) ◽  
pp. 1417
Author(s):  
Azeem Danish ◽  
Robin Gedschold ◽  
Sonja Hinz ◽  
Anke C. Schiedel ◽  
Dominik Thimm ◽  
...  
Keyword(s):  
Gap Junctions ◽  
Small Molecules ◽  
High Throughput Screening ◽  
Cell Communication ◽  
Receptor Activation ◽  
Adenosine A2a Receptor ◽  
Intracellular Camp ◽  
Donor Cells ◽  
A2a Receptor ◽  
Adenosine A2a

Connexin gap junctions (Cx GJs) enable the passage of small molecules and ions between cells and are therefore important for cell-to-cell communication. Their dysfunction is associated with diseases, and small molecules acting as modulators of GJs may therefore be useful as therapeutic drugs. To identify GJ modulators, suitable assays are needed that allow compound screening. In the present study, we established a novel assay utilizing HeLa cells recombinantly expressing Cx43. Donor cells additionally expressing the Gs protein-coupled adenosine A2A receptor, and biosensor cells expressing a cAMP-sensitive GloSensor luciferase were established. Adenosine A2A receptor activation in the donor cells using a selective agonist results in intracellular cAMP production. The negatively charged cAMP migrates via the Cx43 gap junctions to the biosensor cells and can there be measured by the cAMP-dependent luminescence signal. Cx43 GJ modulators can be expected to impact the transfer of cAMP from the donor to the biosensor cells, since cAMP transit is only possible via GJs. The new assay was validated by testing the standard GJ inhibitor carbenoxolon, which showed a concentration-dependent inhibition of the signal and an IC50 value that was consistent with previously reported values. The assay was demonstrated to be suitable for high-throughput screening.

Cancer as development gone awry: the case for bisphenol-A as a carcinogen

2011 ◽  
Vol 2 (1) ◽  
pp. 9-16 ◽  
Author(s):  
C. Sonnenschein ◽  
P. R. Wadia ◽  
B. S. Rubin ◽  
A. M. Soto
Keyword(s):  
Breast Cancer ◽  
Bisphenol A ◽  
Developmental Plasticity ◽  
Empirical Support ◽  
Epidemiological Data ◽  
Additional Treatment ◽  
Tissue Organization ◽  
Estrogen Exposure ◽  
Tissue Organization Field Theory ◽  
Neoplastic Lesions

The discovery of a rare clear cell carcinoma of the vagina in young women gestationally exposed to the estrogen diethylstilbestrol (DES) lent empirical support to the hypothesis that prenatal exposure to xenoestrogens might cause cancer. This fact contradicted two well-accepted notions: (i) mammalian development was merely the unfolding of a genetic program and (ii) only mutagenic agents could cause cancer. The ecological developmental biology (eco–devo) movement revitalized the concept of developmental plasticity through the occurrence of polyphenisms whereby a single genotype produces diverse phenotypes which are determined by environmental cues. Based on the principles of eco–devo and the tissue organization field theory of carcinogenesis, we hypothesized that developmental exposure to xenoestrogens increased the propensity to develop mammary cancer during adulthood. Bisphenol-A (BPA), a ubiquitous xenoestrogen, was chosen as a model for environmental estrogen exposure. In mice, perinatal exposure to environmentally relevant BPA levels induced alterations of the mammary gland architecture which manifested during fetal morphogenesis and throughout life, including the development of pre-neoplastic lesions. In rats, gestational exposure to BPA induced pre-neoplastic lesions and carcinoma in situ that manifested in adulthood in the absence of any additional treatment. Emerging epidemiological data reveal an increased incidence of breast cancer in women exposed to DES during gestation. Hence, both animal experiments and epidemiological data strengthen the hypothesis that fetal exposure to xenoestrogens may be an underlying cause of the increased incidence of breast cancer observed over the past 50 years.

Are gap junctions necessary for cell-to-cell coupling of smooth muscle?: an update

1992 ◽  
Vol 70 (4) ◽  
pp. 481-490 ◽  
Author(s):  
R. E. Garfield ◽  
G. Thilander ◽  
M. G. Blennerhassett ◽  
N. Sakai
Keyword(s):  
Smooth Muscle ◽  
Gap Junctions ◽  
Current Knowledge ◽  
Smooth Muscles ◽  
Cell Communication ◽  
Circular Muscle ◽  
Cell Coupling ◽  
And Function ◽  
Longitudinal Layer ◽  
Cell Cell

Earlier, it was questioned whether gap junctions (GJs) were necessary for cell–cell communication in smooth muscle, and GJs were not seen in some smooth muscles. We reexamined this question in the myometrium and in intestinal smooth muscle, in light of current knowledge of the presence and function of GJs. In the uterus, numerous studies show that an increase in GJ number is associated with the onset of delivery and is required for effective parturition. In all cases, this increase in GJ number and the changes in uterine contractility were correlated with increased electrical and metabolic coupling. Evidence for the much smaller, but detectable, degree of electrical coupling in the preterm uterus is explained by the small (but again detectable) number of GJs present. In the intestine, GJs are readily detected in the circular muscle layer but have not been described in the adjacent longitudinal layer. While our immunohistochemical studies failed to detect GJs in the longitudinal layer, this may not be adequate to prove their absence. Therefore, current knowledge of GJ number and function is adequate to explain cell–cell coupling in the uterus. Although it remains uncertain whether GJs are absent from the longitudinal muscle of the intestine, there is no definitive evidence that cell–cell coupling can occur by means other than GJs.Key words: gap junctions, myometrium, connexins, smooth muscle, cell communication.

Analysis of distribution patterns of gap junctions during development of embryonic chick facial primordia and brain

Development ◽  
1991 ◽  
Vol 111 (2) ◽  
pp. 509-522
Author(s):  
R. Minkoff ◽  
S.B. Parker ◽  
E.L. Hertzberg
Keyword(s):  
Gap Junctions ◽  
Gap Junction ◽  
Uniform Distribution ◽  
Rat Liver ◽  
Connexin 43 ◽  
Cell Communication ◽  
Exterior Surface ◽  
Junction Protein ◽  
Primary Palate ◽  
Gap Junction Protein

Gap junction distribution in the facial primordia of chick embryos at the time of primary palate formation was studied employing indirect immunofluorescence localization with antibodies to gap junction proteins initially identified in rat liver (27 × 10(3) Mr, connexin 32) and heart (43 × 10(3) Mr, connexin 43). Immunolocalization with antibodies to the rat liver gap junction protein (27 × 10(3) Mr) demonstrated a ubiquitous and uniform distribution in all regions of the epithelium and mesenchyme except the nasal placode. In the placodal epithelium, a unique non-random distribution was found characterized by two zones: a very heavy concentration of signal in the superficial layer of cells adjacent to the exterior surface and a region devoid of detectable signal in the interior cell layer adjacent to the mesenchyme. This pattern was seen during all stages of placode invagination that were examined. The separation of gap junctions in distinct cell layers was unique to the nasal placode, and was not found in any other region of the developing primary palate. One other tissue was found that exhibited this pattern-the developing neural epithelium of the brain and retina. These observations suggest the presence of region-specific signaling mechanisms and, possibly, an impedance of cell communication among subpopulations of cells in these structures at critical stages of development. Immunolocalization with antibodies to the ‘heart’ 43 × 10(3) Mr gap junction protein also revealed the presence of gap junction protein in facial primordia and neural epithelium. A non-uniform distribution of immunoreactivity was also observed for connexin 43.

scholarly journals TGF-β1 facilitates cell–cell communication in osteocytes via connexin43- and pannexin1-dependent gap junctions

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Wenjing Liu ◽  
Demao Zhang ◽  
Xin Li ◽  
Liwei Zheng ◽  
Chen Cui ◽  
...  
Keyword(s):  
Gap Junctions ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Lucifer Yellow ◽  
Cell Communication ◽  
Deep Understanding ◽  
Gap Junctional Intercellular Communication ◽  
Tgf Β1 ◽  
Cell Cell

Abstract Connexins and pannexins are two families of channel forming proteins that are able to pass small molecules to achieve communication between cells. While connexins have been recognized to mediate gap junctional intercellular communication (GJIC), pannexins are far less known. Our previous study reported the potential role of TGF-β1 in mediating of connexins in osteocytes in vitro. Herein, we aimed to elucidate the influence of TGF-β1 on cell–cell communication based on gap junctions assembled by connexins and pannexins in vitro and ex vivo. We first showed that TGF-β1 positively affected the elongation of dendritic processes of osteocytes. Our data indicated that TGF-β1 increased expressions of connexin43 (Cx43) and pannexin1 (panx1), which are indispensable for hemichannel formation in gap junctions, in osteocytes in vitro and ex vivo. TGF-β1 enhanced gap junction formation and impacted cell–cell communication in living osteocytes, as indicated by the scrape loading and Lucifer yellow transfer assays. TGF-β1 enhanced the expressions of Cx43 and panx1 via activation of ERK1/2 and Smad3/4 signalling. The TGF-β1-restored expressions of Cx43 and panx1 in osteocytes in the presence of an ERK inhibitor, U0126, further demonstrated the direct participation of Smad3/4 signalling. TGF-β1 increased the accumulation of Smad3 in the nuclear region (immunofluorescence assay) and promoted the enrichment of Smad3 at the binding sites of the promoters of Gja1 (Cx43) and Panx1 (ChIP assay), thereby initiating the enhanced gene expression. These results provide a deep understanding of the molecular mechanisms involved in the modulation of cell–cell communication in osteocytes induced by TGF-β1.

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