Marc Mesnil - Academia.edu (original) (raw)

Papers by Marc Mesnil

Research paper thumbnail of Perinatal exposure to dichloro-bisphenol A alters hepatic lipid composition in mouse: a study by MRI and 1H MRS

Le Centre pour la Communication Scientifique Directe - HAL - Université Francois Rabelais - Tours, 2016

International audienc

Research paper thumbnail of Cx43-Associated Secretome and Interactome Reveal Synergistic Mechanisms for Glioma Migration and MMP3 Activation

Frontiers in Neuroscience, 2019

Extracellular matrix (ECM) remodeling, degradation and glioma cell motility are critical aspects ... more Extracellular matrix (ECM) remodeling, degradation and glioma cell motility are critical aspects of glioblastoma multiforme (GBM). Despite being a rich source of potential biomarkers and targets for therapeutic advance, the dynamic changes occurring within the extracellular environment that are specific to GBM motility have yet to be fully resolved. The gap junction protein connexin43 (Cx43) increases glioma migration and invasion in a variety of in vitro and in vivo models. In this study, the upregulation of Cx43 in C6 glioma cells induced morphological changes and the secretion of proteins associated with cell motility. Demonstrating the selective engagement of ECM remodeling networks, secretome analysis revealed the near-binary increase of osteopontin and matrix metalloproteinase-3 (MMP3), with gelatinase and NFF-3 assays confirming the proteolytic activities. Informatic analysis of interactome and secretome downstream of Cx43 identifies networks of glioma motility that appear to be synergistically engaged. The data presented here implicate ECM remodeling and matrikine signals downstream of Cx43/MMP3/osteopontin and ARK1B10 inhibition as possible avenues to inhibit GBM.

Research paper thumbnail of Consequences of chemoresistance for the herpes simplex virus thymidine kinase/ganciclovir-induced bystander effect in a human small cell lung cancer cell line model

Anticancer research

This paper focuses on the influence of chemoresistance on the herpes simplex virus (HSV-tk)/ganci... more This paper focuses on the influence of chemoresistance on the herpes simplex virus (HSV-tk)/ganciclovir (GCV)-induced bystander effect (BE), as studied in a human small cell lung cancer (SCLC) cell line (GLC4) and its sublines with in vitro acquired resistance to adriamycin (GLC4/ADR), mitoxantrone (GLC4/MITO) and cisplatin (GLC4/CDDP). Chemoresistance for adriamycin, mitoxantrone and cisplatin significantly changed GCV sensitivity. A significant BE was found in all GLC4 cell lines. Compared to the parental GLC4 cell line, the BE was significantly higher only for the GLC4/ADR cell line. No expression of the nucleoside transporters MRP4 and MRP5 was detected. In all cell lines expression of connexin 43 was found, but modulation of gap junctional intercellular communication (GJIC) by 18-alpha-glycyrrhetinic acid did not significantly change the BE in any of the GLC4 cell lines. In conclusion, chemoresistance can influence the HSV-tk/GCV-induced BE, which seems not to be related to dif...

Research paper thumbnail of Connexin-dependent inter-cellular communication increases invasion and dissemination of Shigella in epithelial cells

Nature Cell Biology, 2003

Shigella flexneri, the causative agent of bacillar dystentery, invades the colonic mucosa where i... more Shigella flexneri, the causative agent of bacillar dystentery, invades the colonic mucosa where it elicits an intense inflammatory reaction responsible for destruction of the epithelium. During cell invasion, contact with host cells activates the type-III secretion of the Shigella IpaB and IpaC proteins. IpaB and IpaC are inserted into host cell plasma membranes and trigger initial signals that result in actin polymerization, while allowing cytosolic access of other bacterial effectors that further reorganize the cytoskeleton. After internalization, Shigella moves intracellularly and forms protrusions that infect neighbouring cells, promoting bacterial dissemination across the epithelium. Here, we show that during cell invasion, Shigella induces transient peaks in intracellular calcium concentration that are dependent on a functional type-III secretory apparatus. In addition, Shigella invasion induces the opening of Connexin 26 (Cx26) hemichannels in an actin- and phospholipase-C-dependent manner, allowing release of ATP into the medium. The released ATP, in turn, increases bacterial invasion and spreading, as well as calcium signalling induced by Shigella. These results provide evidence that pathogen-induced opening of connexin channels promotes signalling events that favour bacterial invasion and dissemination.

Research paper thumbnail of The modulation of gap-junctional intercellular communication by lipid rafts

Biochimica et Biophysica Acta (BBA) - Biomembranes, 2012

Lipid rafts are specific microdomains of plasma membrane which are enriched in cholesterol and sp... more Lipid rafts are specific microdomains of plasma membrane which are enriched in cholesterol and sphingolipids. These domains seem to favour the interactions of particular proteins and the regulation of signalling pathways in the cells. Recent data have shown that among the proteins, which are preferentially localized in lipid rafts, are connexins that are the structural proteins of gap junctions. Since gap junctional intercellular communication is involved in various cellular processes and pathologies such as cancer, we were interested to review the various observations concerning this specific localization of connexins in lipid rafts and its consequences on gap junctional intercellular communication capacity. In particular, we will focus our discussion on the role of the lipid raft-connexin connection in cancer progression. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.

Research paper thumbnail of Connexins in cancer: bridging the gap to the clinic

Oncogene, 2019

Gap junctions comprise arrays of intercellular channels formed by connexin proteins and provide f... more Gap junctions comprise arrays of intercellular channels formed by connexin proteins and provide for the direct communication between adjacent cells. This type of intercellular communication permits the coordination of cellular activities and plays key roles in the control of cell growth and differentiation and in the maintenance of tissue homoeostasis. After more than 50 years, deciphering the links among connexins, gap junctions and cancer, researchers are now beginning to translate this knowledge to the clinic. The emergence of new strategies for connexin targeting, combined with an improved understanding of the molecular bases underlying the dysregulation of connexins during cancer development, offers novel opportunities for clinical applications. However, different connexin isoforms have diverse channel-dependent and-independent functions that are tissue and stage specific. This can elicit both pro-and anti-tumorigenic effects that engender significant challenges in the path towards personalised medicine. Here, we review the current understanding of the role of connexins and gap junctions in cancer, with particular focus on the recent progress made in determining their prognostic and therapeutic potential.

Research paper thumbnail of A Tumor Suppressor Gene , Cx 26 , Also Mediates the Bystander Effect in HeLa Cells 1

The connexin 26 (Cx26) gene suppresses the growth of HeLa cells in vitro and in vivo. We explored... more The connexin 26 (Cx26) gene suppresses the growth of HeLa cells in vitro and in vivo. We explored the possibility that the Cx26genenot only suppresses growth but can also mediate the bystander effect that is observed in some gene therapy. In gene therapy mediated by the herpes simplex virus thymidine kinase, the toxicity of ganciclovir affects not only the cells transduced with the gene but also affects neighboring tumor cells; it has been suggested that gap junctional intercellular communication (GJIC) may play a role in such a bystander effect. HeLa cells expressing the Cx26 gene(Cx26―@) or not expressingthe Cx26genewere transfected with the herpes simplex virus thymidine kinase (tki gene, producing Cx26-tlC, Cx26'-tk―, Cx26@-tk', and Cx26@-tk' cells. By making different kinds of cocultures of these cells, we observed a clear bystander killing effect, assessed by the neutral red toxicity test, in the coculture of Cx26@-tk/Cx26@-tk@ cells. The bystander effect was m...

Research paper thumbnail of Involvement of the Gap Junction Protein, Connexin43, in the Formation and Function of Invadopodia in the Human U251 Glioblastoma Cell Line

Cells, Jan 3, 2020

The resistance of glioblastomas to treatments is mainly the consequence of their invasive capacit... more The resistance of glioblastomas to treatments is mainly the consequence of their invasive capacities. Therefore, in order to better treat these tumors, it is important to understand the molecular mechanisms which are responsible for this behavior. Previous work suggested that gap junction proteins, the connexins, facilitate the aggressive nature of glioma cells. Here, we show that one of them—connexin43 (Cx43)—is implicated in the formation and function of invadopodia responsible for invasion capacity of U251 human glioblastoma cells. Immunofluorescent approaches—combined with confocal analyses—revealed that Cx43 was detected in all the formation stages of invadopodia exhibiting proteolytic activity. Clearly, Cx43 appeared to be localized in invadopodia at low cell density and less associated with the establishment of gap junctions. Accordingly, lower extracellular matrix degradation correlated with less mature invadopodia and MMP2 activity when Cx43 expression was decreased by shRNA strategies. Moreover, the kinetics of invadopodia formation could be dependent on Cx43 dynamic interactions with partners including Src and cortactin. Interestingly, it also appeared that invadopodia formation and MMP2 activity are dependent on Cx43 hemichannel activity. In conclusion, these results reveal that Cx43 might be involved in the formation and function of the invadopodia of U251 glioblastoma cells.

Research paper thumbnail of Connexins and Pannexins: Important Players in Tumorigenesis, Metastasis and Potential Therapeutics

International Journal of Molecular Sciences

Since their characterization more than five decades ago, gap junctions and their structural prote... more Since their characterization more than five decades ago, gap junctions and their structural proteins-the connexins-have been associated with cancer cell growth. During that period, the accumulation of data and molecular knowledge about this association revealed an apparent contradictory relationship between them and cancer. It appeared that if gap junctions or connexins can down regulate cancer cell growth they can be also implied in the migration, invasion and metastatic dissemination of cancer cells. Interestingly, in all these situations, connexins seem to be involved through various mechanisms in which they can act either as gap-junctional intercellular communication mediators, modulators of signalling pathways through their interactome, or as hemichannels, which mediate autocrine/paracrine communication. This complex involvement of connexins in cancer progression is even more complicated by the fact that their hemichannel function may overlap with other gap junction-related proteins, the pannexins. Despite this complexity, the possible involvements of connexins and pannexins in cancer progression and the elucidation of the mechanisms they control may lead to use them as new targets to control cancer progression. In this review, the involvements of connexins and pannexins in these different topics (cancer cell growth, invasion/metastasis process, possible cancer therapeutic targets) are discussed.

Research paper thumbnail of Pannexin-1 in Human Lymphatic Endothelial Cells Regulates Lymphangiogenesis

International journal of molecular sciences, Jan 24, 2018

The molecular mechanisms governing the formation of lymphatic vasculature are not yet well unders... more The molecular mechanisms governing the formation of lymphatic vasculature are not yet well understood. Pannexins are transmembrane proteins that form channels which allow for diffusion of ions and small molecules (<1 kDa) between the extracellular space and the cytosol. The expression and function of pannexins in blood vessels have been studied in the last few decades. Meanwhile, no studies have been conducted to evaluate the role of pannexins during human lymphatic vessel formation. Here we show, using primary human dermal lymphatic endothelial cells (HDLECs), pharmacological tools (probenecid, Brilliant Blue FCF, mimetic peptides [Panx]) and siRNA-mediated knockdown that Pannexin-1 is necessary for capillary tube formation on Matrigel and for VEGF-C-induced invasion. These results newly identify Pannexin-1 as a protein highly expressed in HDLECs and its requirement during in vitro lymphangiogenesis.

Research paper thumbnail of Cell-cell communication and growth control of normal and cancer cells: Evidence and hypothesis

Molecular Carcinogenesis, 1993

... Marc Mesnil,; Hiroshi Yamasaki,; Allan Balmain,; J. Carl Barrett,; Harold Moses. Article firs... more ... Marc Mesnil,; Hiroshi Yamasaki,; Allan Balmain,; J. Carl Barrett,; Harold Moses. Article first published online: 20 JUL 2006. DOI: 10.1002/mc.2940070103. Copyright © 1993 Wiley-Liss, Inc., A Wiley Company. Issue. Molecular Carcinogenesis. Volume 7, Issue 1, pages 14–17, 1993 ...

Research paper thumbnail of 488 Quantitative proteomics reveals secreted factors governing enhanced motility in rat C6 glioma cells expressing connexin43

Ejc Supplements - EJC SUPPL, 2010

ErbB2 expression with specific siRNA blocked the PGE 2-induced amplification of cyclin D1 express... more ErbB2 expression with specific siRNA blocked the PGE 2-induced amplification of cyclin D1 expression and DNA synthesis in response to EGF. Conclusion: The results suggest that the upregulation by PGE 2 of the mitogenic response of hepatocytes to EGF may at least in part be mediated by increased expression of ErbB2. 488 Quantitative proteomics reveals secreted factors governing enhanced motility in rat C6 glioma cells expressing connexin43

Research paper thumbnail of Endothelin1-Induced Ca2+ Mobilization Is Altered in Calvarial Osteoblastic Cells of Cx43+/− Mice

Journal of Membrane Biology, 2007

Research paper thumbnail of Defective Gap Junctional Intercellular Communication In the Carcinogenic Process

Biochimica et Biophysica …, 2005

Gap junctions are membrane structures made of intercellular channels which permit the diffusion f... more Gap junctions are membrane structures made of intercellular channels which permit the diffusion from cytoplasm to cytoplasm of small hydrophilic molecules. Nearly 40 years ago, the loss of functional gap junctions has been described in cancer cells and led to the hypothesis that ...

Research paper thumbnail of A tumor suppressor gene, Cx26, also mediates the bystander effect in HeLa cells

Cancer Research, Jul 15, 1997

The connexin 26 (Cx26) gene suppresses the growth of HeLa cells in vitro and in vivo. We explored... more The connexin 26 (Cx26) gene suppresses the growth of HeLa cells in vitro and in vivo. We explored the possibility that the Cx26 gene not only suppresses growth but can also mediate the bystander effect that is observed in some gene therapy. In gene therapy mediated by the herpes simplex virus thymidine kinase, the toxicity of ganciclovir affects not only the cells transduced with the gene but also affects neighboring tumor cells; it has been suggested that gap junctional intercellular communication (GJIC) may play a role in such a bystander effect. HeLa cells expressing the Cx26 gene (Cx26+) or not expressing the Cx26 gene were transfected with the herpes simplex virus thymidine kinase (tk+) gene, producing Cx26(-)-tk-, Cx26(-)-tk+, Cx26+-tk-, and Cx26+-tk+ cells. By making different kinds of cocultures of these cells, we observed a clear bystander killing effect, assessed by the neutral red toxicity test, in the coculture of Cx26+-tk-/Cx26+-tk+ cells. The bystander effect was marke...

Research paper thumbnail of Is the Exposome Involved in Brain Disorders through the Serotoninergic System?

Biomedicines

Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine acting as a neurotransmitter in the... more Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine acting as a neurotransmitter in the central nervous system (CNS), local mediator in the gut, and vasoactive agent in the blood. It has been linked to a variety of CNS functions and is implicated in many CNS and psychiatric disorders. The high comorbidity between some neuropathies can be partially understood by the fact that these diseases share a common etiology involving the serotoninergic system. In addition to its well-known functions, serotonin has been shown to be a mitogenic factor for a wide range of normal and tumor cells, including glioma cells, in vitro. The developing CNS of fetus and newborn is particularly susceptible to the deleterious effects of neurotoxic substances in our environment, and perinatal exposure could result in the later development of diseases, a hypothesis known as the developmental origin of health and disease. Some of these substances affect the serotoninergic system and could therefore be...

Research paper thumbnail of Serotonin and human cancer: A critical view

Research paper thumbnail of Gestational and lactational exposure to dichlorinated bisphenol A induces early alterations of hepatic lipid composition in mice

Magma (New York, N.Y.), Jan 20, 2018

Using non-invasive magnetic resonance (MR) techniques and a histological approach, we assessed th... more Using non-invasive magnetic resonance (MR) techniques and a histological approach, we assessed the outcomes of perinatal exposure at a low dose of 3,3'-DCBPA (2-chloro-4-[1-(3-chloro-4-hydroxyphenyl)-1-methylethyl]phenol) and/or 3,5-DCBPA (2,6-dichloro-4-[1-(4-hydroxyphenyl)-1-methylethyl]phenol) on mice livers. Fertilized female Swiss mice were injected intraperitoneally during gestation and lactation with either vehicle control, 20 μg/kg/day of BPA, 3,5-DCBPA, 3,3'-DCBPA or a mixture (mix-DCBPA). Complementary methods were used to evaluate, in male and female pups, (1) liver structure by texture analysis of images obtained through MR imaging (MRI) and histology, (2) hepatic lipid composition through in vivoH MR spectroscopy (H MRS). Principal component analysis of texture parameters showed no structural modification of the liver with BPA and DCBPA treatments. Accordingly, no hepatic microvesicular steatosis was observed through hematoxylin-eosin staining. Compared to contr...

Research paper thumbnail of Targeting Gap Junctions: New Insights in the Treatment of Major Depressive Disorder

Current medicinal chemistry, Jan 26, 2018

Major depressive disorder (MDD) is a multifactorial chronic and debilitating mood disease with hi... more Major depressive disorder (MDD) is a multifactorial chronic and debilitating mood disease with high lifetime prevalence and associated with excess mortality. Treatments of this disease are not effective in all patients showing the need to find new therapeutic targets. This review aims to update our knowledge about the involvement of astroglial gap junctions and hemichannels in MDD and to show how they have become potential targets for the treatment of this pathology. The method applied in this review includes a systematic compilation of the relevant literature. The use of rodent models of depression, gene analysis of hippocampal tissues of MDD patients and post-mortem studies of brains from MDD patients suggest that astrocytic gap junction dysfunction may be part of MDD etiologies. Chronic antidepressant treatments of rats, rat cultured cortical astrocytes and human astrocytoma cell lines support the hypothesis that the up-regulation of gap junctional coupling between astrocytes cou...

Research paper thumbnail of The connexin 43 C-terminus: A tail of many tales

Biochimica et Biophysica Acta (BBA) - Biomembranes

Connexins are chordate gap junction channel proteins that, by enabling direct communication betwe... more Connexins are chordate gap junction channel proteins that, by enabling direct communication between the cytosols of adjacent cells, create a unique cell signalling network. Gap junctional intercellular communication (GJIC) has important roles in controlling cell growth and differentiation and in tissue development and homeostasis. Moreover, several non-canonical connexin functions unrelated to GJIC have been discovered. Of the 21 members of the human connexin family, connexin 43 (Cx43) is the most widely expressed and studied. The long cytosolic C-terminus (CT) of Cx43 is subject to extensive post-translational modifications that modulate its intracellular trafficking and gap junction channel gating. Moreover, the Cx43 CT contains multiple domains involved in protein interactions that permit crosstalk between Cx43 and cytoskeletal and regulatory proteins. These domains endow Cx43 with the capacity to affect cell growth and differentiation independently of GJIC. Here, we review the current understanding of the regulation and unique functions of the Cx43 CT, both as an essential component of full-length Cx43 and as an independent signalling hub. We highlight the complex regulatory and signalling networks controlled by the Cx43 CT, including the extensive protein interactome that underlies both gap junction channel-dependent and -independent functions. We discuss these data in relation to the recent discovery of the direct translation of specific truncated forms of Cx43. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve.

Research paper thumbnail of Perinatal exposure to dichloro-bisphenol A alters hepatic lipid composition in mouse: a study by MRI and 1H MRS

Le Centre pour la Communication Scientifique Directe - HAL - Université Francois Rabelais - Tours, 2016

International audienc

Research paper thumbnail of Cx43-Associated Secretome and Interactome Reveal Synergistic Mechanisms for Glioma Migration and MMP3 Activation

Frontiers in Neuroscience, 2019

Extracellular matrix (ECM) remodeling, degradation and glioma cell motility are critical aspects ... more Extracellular matrix (ECM) remodeling, degradation and glioma cell motility are critical aspects of glioblastoma multiforme (GBM). Despite being a rich source of potential biomarkers and targets for therapeutic advance, the dynamic changes occurring within the extracellular environment that are specific to GBM motility have yet to be fully resolved. The gap junction protein connexin43 (Cx43) increases glioma migration and invasion in a variety of in vitro and in vivo models. In this study, the upregulation of Cx43 in C6 glioma cells induced morphological changes and the secretion of proteins associated with cell motility. Demonstrating the selective engagement of ECM remodeling networks, secretome analysis revealed the near-binary increase of osteopontin and matrix metalloproteinase-3 (MMP3), with gelatinase and NFF-3 assays confirming the proteolytic activities. Informatic analysis of interactome and secretome downstream of Cx43 identifies networks of glioma motility that appear to be synergistically engaged. The data presented here implicate ECM remodeling and matrikine signals downstream of Cx43/MMP3/osteopontin and ARK1B10 inhibition as possible avenues to inhibit GBM.

Research paper thumbnail of Consequences of chemoresistance for the herpes simplex virus thymidine kinase/ganciclovir-induced bystander effect in a human small cell lung cancer cell line model

Anticancer research

This paper focuses on the influence of chemoresistance on the herpes simplex virus (HSV-tk)/ganci... more This paper focuses on the influence of chemoresistance on the herpes simplex virus (HSV-tk)/ganciclovir (GCV)-induced bystander effect (BE), as studied in a human small cell lung cancer (SCLC) cell line (GLC4) and its sublines with in vitro acquired resistance to adriamycin (GLC4/ADR), mitoxantrone (GLC4/MITO) and cisplatin (GLC4/CDDP). Chemoresistance for adriamycin, mitoxantrone and cisplatin significantly changed GCV sensitivity. A significant BE was found in all GLC4 cell lines. Compared to the parental GLC4 cell line, the BE was significantly higher only for the GLC4/ADR cell line. No expression of the nucleoside transporters MRP4 and MRP5 was detected. In all cell lines expression of connexin 43 was found, but modulation of gap junctional intercellular communication (GJIC) by 18-alpha-glycyrrhetinic acid did not significantly change the BE in any of the GLC4 cell lines. In conclusion, chemoresistance can influence the HSV-tk/GCV-induced BE, which seems not to be related to dif...

Research paper thumbnail of Connexin-dependent inter-cellular communication increases invasion and dissemination of Shigella in epithelial cells

Nature Cell Biology, 2003

Shigella flexneri, the causative agent of bacillar dystentery, invades the colonic mucosa where i... more Shigella flexneri, the causative agent of bacillar dystentery, invades the colonic mucosa where it elicits an intense inflammatory reaction responsible for destruction of the epithelium. During cell invasion, contact with host cells activates the type-III secretion of the Shigella IpaB and IpaC proteins. IpaB and IpaC are inserted into host cell plasma membranes and trigger initial signals that result in actin polymerization, while allowing cytosolic access of other bacterial effectors that further reorganize the cytoskeleton. After internalization, Shigella moves intracellularly and forms protrusions that infect neighbouring cells, promoting bacterial dissemination across the epithelium. Here, we show that during cell invasion, Shigella induces transient peaks in intracellular calcium concentration that are dependent on a functional type-III secretory apparatus. In addition, Shigella invasion induces the opening of Connexin 26 (Cx26) hemichannels in an actin- and phospholipase-C-dependent manner, allowing release of ATP into the medium. The released ATP, in turn, increases bacterial invasion and spreading, as well as calcium signalling induced by Shigella. These results provide evidence that pathogen-induced opening of connexin channels promotes signalling events that favour bacterial invasion and dissemination.

Research paper thumbnail of The modulation of gap-junctional intercellular communication by lipid rafts

Biochimica et Biophysica Acta (BBA) - Biomembranes, 2012

Lipid rafts are specific microdomains of plasma membrane which are enriched in cholesterol and sp... more Lipid rafts are specific microdomains of plasma membrane which are enriched in cholesterol and sphingolipids. These domains seem to favour the interactions of particular proteins and the regulation of signalling pathways in the cells. Recent data have shown that among the proteins, which are preferentially localized in lipid rafts, are connexins that are the structural proteins of gap junctions. Since gap junctional intercellular communication is involved in various cellular processes and pathologies such as cancer, we were interested to review the various observations concerning this specific localization of connexins in lipid rafts and its consequences on gap junctional intercellular communication capacity. In particular, we will focus our discussion on the role of the lipid raft-connexin connection in cancer progression. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.

Research paper thumbnail of Connexins in cancer: bridging the gap to the clinic

Oncogene, 2019

Gap junctions comprise arrays of intercellular channels formed by connexin proteins and provide f... more Gap junctions comprise arrays of intercellular channels formed by connexin proteins and provide for the direct communication between adjacent cells. This type of intercellular communication permits the coordination of cellular activities and plays key roles in the control of cell growth and differentiation and in the maintenance of tissue homoeostasis. After more than 50 years, deciphering the links among connexins, gap junctions and cancer, researchers are now beginning to translate this knowledge to the clinic. The emergence of new strategies for connexin targeting, combined with an improved understanding of the molecular bases underlying the dysregulation of connexins during cancer development, offers novel opportunities for clinical applications. However, different connexin isoforms have diverse channel-dependent and-independent functions that are tissue and stage specific. This can elicit both pro-and anti-tumorigenic effects that engender significant challenges in the path towards personalised medicine. Here, we review the current understanding of the role of connexins and gap junctions in cancer, with particular focus on the recent progress made in determining their prognostic and therapeutic potential.

Research paper thumbnail of A Tumor Suppressor Gene , Cx 26 , Also Mediates the Bystander Effect in HeLa Cells 1

The connexin 26 (Cx26) gene suppresses the growth of HeLa cells in vitro and in vivo. We explored... more The connexin 26 (Cx26) gene suppresses the growth of HeLa cells in vitro and in vivo. We explored the possibility that the Cx26genenot only suppresses growth but can also mediate the bystander effect that is observed in some gene therapy. In gene therapy mediated by the herpes simplex virus thymidine kinase, the toxicity of ganciclovir affects not only the cells transduced with the gene but also affects neighboring tumor cells; it has been suggested that gap junctional intercellular communication (GJIC) may play a role in such a bystander effect. HeLa cells expressing the Cx26 gene(Cx26―@) or not expressingthe Cx26genewere transfected with the herpes simplex virus thymidine kinase (tki gene, producing Cx26-tlC, Cx26'-tk―, Cx26@-tk', and Cx26@-tk' cells. By making different kinds of cocultures of these cells, we observed a clear bystander killing effect, assessed by the neutral red toxicity test, in the coculture of Cx26@-tk/Cx26@-tk@ cells. The bystander effect was m...

Research paper thumbnail of Involvement of the Gap Junction Protein, Connexin43, in the Formation and Function of Invadopodia in the Human U251 Glioblastoma Cell Line

Cells, Jan 3, 2020

The resistance of glioblastomas to treatments is mainly the consequence of their invasive capacit... more The resistance of glioblastomas to treatments is mainly the consequence of their invasive capacities. Therefore, in order to better treat these tumors, it is important to understand the molecular mechanisms which are responsible for this behavior. Previous work suggested that gap junction proteins, the connexins, facilitate the aggressive nature of glioma cells. Here, we show that one of them—connexin43 (Cx43)—is implicated in the formation and function of invadopodia responsible for invasion capacity of U251 human glioblastoma cells. Immunofluorescent approaches—combined with confocal analyses—revealed that Cx43 was detected in all the formation stages of invadopodia exhibiting proteolytic activity. Clearly, Cx43 appeared to be localized in invadopodia at low cell density and less associated with the establishment of gap junctions. Accordingly, lower extracellular matrix degradation correlated with less mature invadopodia and MMP2 activity when Cx43 expression was decreased by shRNA strategies. Moreover, the kinetics of invadopodia formation could be dependent on Cx43 dynamic interactions with partners including Src and cortactin. Interestingly, it also appeared that invadopodia formation and MMP2 activity are dependent on Cx43 hemichannel activity. In conclusion, these results reveal that Cx43 might be involved in the formation and function of the invadopodia of U251 glioblastoma cells.

Research paper thumbnail of Connexins and Pannexins: Important Players in Tumorigenesis, Metastasis and Potential Therapeutics

International Journal of Molecular Sciences

Since their characterization more than five decades ago, gap junctions and their structural prote... more Since their characterization more than five decades ago, gap junctions and their structural proteins-the connexins-have been associated with cancer cell growth. During that period, the accumulation of data and molecular knowledge about this association revealed an apparent contradictory relationship between them and cancer. It appeared that if gap junctions or connexins can down regulate cancer cell growth they can be also implied in the migration, invasion and metastatic dissemination of cancer cells. Interestingly, in all these situations, connexins seem to be involved through various mechanisms in which they can act either as gap-junctional intercellular communication mediators, modulators of signalling pathways through their interactome, or as hemichannels, which mediate autocrine/paracrine communication. This complex involvement of connexins in cancer progression is even more complicated by the fact that their hemichannel function may overlap with other gap junction-related proteins, the pannexins. Despite this complexity, the possible involvements of connexins and pannexins in cancer progression and the elucidation of the mechanisms they control may lead to use them as new targets to control cancer progression. In this review, the involvements of connexins and pannexins in these different topics (cancer cell growth, invasion/metastasis process, possible cancer therapeutic targets) are discussed.

Research paper thumbnail of Pannexin-1 in Human Lymphatic Endothelial Cells Regulates Lymphangiogenesis

International journal of molecular sciences, Jan 24, 2018

The molecular mechanisms governing the formation of lymphatic vasculature are not yet well unders... more The molecular mechanisms governing the formation of lymphatic vasculature are not yet well understood. Pannexins are transmembrane proteins that form channels which allow for diffusion of ions and small molecules (<1 kDa) between the extracellular space and the cytosol. The expression and function of pannexins in blood vessels have been studied in the last few decades. Meanwhile, no studies have been conducted to evaluate the role of pannexins during human lymphatic vessel formation. Here we show, using primary human dermal lymphatic endothelial cells (HDLECs), pharmacological tools (probenecid, Brilliant Blue FCF, mimetic peptides [Panx]) and siRNA-mediated knockdown that Pannexin-1 is necessary for capillary tube formation on Matrigel and for VEGF-C-induced invasion. These results newly identify Pannexin-1 as a protein highly expressed in HDLECs and its requirement during in vitro lymphangiogenesis.

Research paper thumbnail of Cell-cell communication and growth control of normal and cancer cells: Evidence and hypothesis

Molecular Carcinogenesis, 1993

... Marc Mesnil,; Hiroshi Yamasaki,; Allan Balmain,; J. Carl Barrett,; Harold Moses. Article firs... more ... Marc Mesnil,; Hiroshi Yamasaki,; Allan Balmain,; J. Carl Barrett,; Harold Moses. Article first published online: 20 JUL 2006. DOI: 10.1002/mc.2940070103. Copyright © 1993 Wiley-Liss, Inc., A Wiley Company. Issue. Molecular Carcinogenesis. Volume 7, Issue 1, pages 14–17, 1993 ...

Research paper thumbnail of 488 Quantitative proteomics reveals secreted factors governing enhanced motility in rat C6 glioma cells expressing connexin43

Ejc Supplements - EJC SUPPL, 2010

ErbB2 expression with specific siRNA blocked the PGE 2-induced amplification of cyclin D1 express... more ErbB2 expression with specific siRNA blocked the PGE 2-induced amplification of cyclin D1 expression and DNA synthesis in response to EGF. Conclusion: The results suggest that the upregulation by PGE 2 of the mitogenic response of hepatocytes to EGF may at least in part be mediated by increased expression of ErbB2. 488 Quantitative proteomics reveals secreted factors governing enhanced motility in rat C6 glioma cells expressing connexin43

Research paper thumbnail of Endothelin1-Induced Ca2+ Mobilization Is Altered in Calvarial Osteoblastic Cells of Cx43+/− Mice

Journal of Membrane Biology, 2007

Research paper thumbnail of Defective Gap Junctional Intercellular Communication In the Carcinogenic Process

Biochimica et Biophysica …, 2005

Gap junctions are membrane structures made of intercellular channels which permit the diffusion f... more Gap junctions are membrane structures made of intercellular channels which permit the diffusion from cytoplasm to cytoplasm of small hydrophilic molecules. Nearly 40 years ago, the loss of functional gap junctions has been described in cancer cells and led to the hypothesis that ...

Research paper thumbnail of A tumor suppressor gene, Cx26, also mediates the bystander effect in HeLa cells

Cancer Research, Jul 15, 1997

The connexin 26 (Cx26) gene suppresses the growth of HeLa cells in vitro and in vivo. We explored... more The connexin 26 (Cx26) gene suppresses the growth of HeLa cells in vitro and in vivo. We explored the possibility that the Cx26 gene not only suppresses growth but can also mediate the bystander effect that is observed in some gene therapy. In gene therapy mediated by the herpes simplex virus thymidine kinase, the toxicity of ganciclovir affects not only the cells transduced with the gene but also affects neighboring tumor cells; it has been suggested that gap junctional intercellular communication (GJIC) may play a role in such a bystander effect. HeLa cells expressing the Cx26 gene (Cx26+) or not expressing the Cx26 gene were transfected with the herpes simplex virus thymidine kinase (tk+) gene, producing Cx26(-)-tk-, Cx26(-)-tk+, Cx26+-tk-, and Cx26+-tk+ cells. By making different kinds of cocultures of these cells, we observed a clear bystander killing effect, assessed by the neutral red toxicity test, in the coculture of Cx26+-tk-/Cx26+-tk+ cells. The bystander effect was marke...

Research paper thumbnail of Is the Exposome Involved in Brain Disorders through the Serotoninergic System?

Biomedicines

Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine acting as a neurotransmitter in the... more Serotonin (5-hydroxytryptamine, 5-HT) is a biogenic monoamine acting as a neurotransmitter in the central nervous system (CNS), local mediator in the gut, and vasoactive agent in the blood. It has been linked to a variety of CNS functions and is implicated in many CNS and psychiatric disorders. The high comorbidity between some neuropathies can be partially understood by the fact that these diseases share a common etiology involving the serotoninergic system. In addition to its well-known functions, serotonin has been shown to be a mitogenic factor for a wide range of normal and tumor cells, including glioma cells, in vitro. The developing CNS of fetus and newborn is particularly susceptible to the deleterious effects of neurotoxic substances in our environment, and perinatal exposure could result in the later development of diseases, a hypothesis known as the developmental origin of health and disease. Some of these substances affect the serotoninergic system and could therefore be...

Research paper thumbnail of Serotonin and human cancer: A critical view

Research paper thumbnail of Gestational and lactational exposure to dichlorinated bisphenol A induces early alterations of hepatic lipid composition in mice

Magma (New York, N.Y.), Jan 20, 2018

Using non-invasive magnetic resonance (MR) techniques and a histological approach, we assessed th... more Using non-invasive magnetic resonance (MR) techniques and a histological approach, we assessed the outcomes of perinatal exposure at a low dose of 3,3'-DCBPA (2-chloro-4-[1-(3-chloro-4-hydroxyphenyl)-1-methylethyl]phenol) and/or 3,5-DCBPA (2,6-dichloro-4-[1-(4-hydroxyphenyl)-1-methylethyl]phenol) on mice livers. Fertilized female Swiss mice were injected intraperitoneally during gestation and lactation with either vehicle control, 20 μg/kg/day of BPA, 3,5-DCBPA, 3,3'-DCBPA or a mixture (mix-DCBPA). Complementary methods were used to evaluate, in male and female pups, (1) liver structure by texture analysis of images obtained through MR imaging (MRI) and histology, (2) hepatic lipid composition through in vivoH MR spectroscopy (H MRS). Principal component analysis of texture parameters showed no structural modification of the liver with BPA and DCBPA treatments. Accordingly, no hepatic microvesicular steatosis was observed through hematoxylin-eosin staining. Compared to contr...

Research paper thumbnail of Targeting Gap Junctions: New Insights in the Treatment of Major Depressive Disorder

Current medicinal chemistry, Jan 26, 2018

Major depressive disorder (MDD) is a multifactorial chronic and debilitating mood disease with hi... more Major depressive disorder (MDD) is a multifactorial chronic and debilitating mood disease with high lifetime prevalence and associated with excess mortality. Treatments of this disease are not effective in all patients showing the need to find new therapeutic targets. This review aims to update our knowledge about the involvement of astroglial gap junctions and hemichannels in MDD and to show how they have become potential targets for the treatment of this pathology. The method applied in this review includes a systematic compilation of the relevant literature. The use of rodent models of depression, gene analysis of hippocampal tissues of MDD patients and post-mortem studies of brains from MDD patients suggest that astrocytic gap junction dysfunction may be part of MDD etiologies. Chronic antidepressant treatments of rats, rat cultured cortical astrocytes and human astrocytoma cell lines support the hypothesis that the up-regulation of gap junctional coupling between astrocytes cou...

Research paper thumbnail of The connexin 43 C-terminus: A tail of many tales

Biochimica et Biophysica Acta (BBA) - Biomembranes

Connexins are chordate gap junction channel proteins that, by enabling direct communication betwe... more Connexins are chordate gap junction channel proteins that, by enabling direct communication between the cytosols of adjacent cells, create a unique cell signalling network. Gap junctional intercellular communication (GJIC) has important roles in controlling cell growth and differentiation and in tissue development and homeostasis. Moreover, several non-canonical connexin functions unrelated to GJIC have been discovered. Of the 21 members of the human connexin family, connexin 43 (Cx43) is the most widely expressed and studied. The long cytosolic C-terminus (CT) of Cx43 is subject to extensive post-translational modifications that modulate its intracellular trafficking and gap junction channel gating. Moreover, the Cx43 CT contains multiple domains involved in protein interactions that permit crosstalk between Cx43 and cytoskeletal and regulatory proteins. These domains endow Cx43 with the capacity to affect cell growth and differentiation independently of GJIC. Here, we review the current understanding of the regulation and unique functions of the Cx43 CT, both as an essential component of full-length Cx43 and as an independent signalling hub. We highlight the complex regulatory and signalling networks controlled by the Cx43 CT, including the extensive protein interactome that underlies both gap junction channel-dependent and -independent functions. We discuss these data in relation to the recent discovery of the direct translation of specific truncated forms of Cx43. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve.