Conflicting Roles of Connexin43 in Tumor-Induced Inflammation and Cancer Pathology

Uzu, Miaki; Sin, Wun Chey; Shimizu, Ayaka; Sato, Hiromi

doi:10.20944/preprints201803.0076.v1

2018

DOI: 10.20944/preprints201803.0076.v1

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Conflicting Roles of Connexin43 in Tumor-Induced Inflammation and Cancer Pathology

Miaki Uzu¹,

Wun Chey Sin²,

Ayaka Shimizu³

et al.

Abstract: Abstract:The tumor microenvironment is known to have increased levels of cytokines and 11 metabolites, such as glutamate, due to their release from the surrounding cells. A normal cell around 12 the tumor that responds to the inflammatory environment is likely to be subsequently altered. We 13 will discuss how these abnormalities will support tumor survival via the actions of gap junctions

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Cited by 9 publications

References 98 publications

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Connexins in Cancer: Jekyll or Hyde?

2020

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The expression, localization, and function of connexins, the protein subunits that comprise gap junctions, are often altered in cancer. In addition to cell–cell coupling through gap junction channels, connexins also form hemichannels that allow communication between the cell and the extracellular space and perform non-junctional intracellular activities. Historically, connexins have been considered tumor suppressors; however, they can also serve tumor-promoting functions in some contexts. Here, we review the literature surrounding connexins in cancer cells in terms of specific connexin functions and propose that connexins function upstream of most, if not all, of the hallmarks of cancer. The development of advanced connexin targeting approaches remains an opportunity for the field to further interrogate the role of connexins in cancer phenotypes, particularly through the use of in vivo models. More specific modulators of connexin function will both help elucidate the functions of connexins in cancer and advance connexin-specific therapies in the clinic.

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Connexins in Cancer: Jekyll or Hyde?

2020

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Facets of Communication: Gap Junction Ultrastructure and Function in Cancer Stem Cells and Tumor Cells

Beckmann

Hainz

Tschernig

et al. 2019

Cancers

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Gap junction proteins are expressed in cancer stem cells and non-stem cancer cells of many tumors. As the morphology and assembly of gap junction channels are crucial for their function in intercellular communication, one focus of our review is to outline the data on gap junction plaque morphology available for cancer cells. Electron microscopic studies and freeze-fracture analyses on gap junction ultrastructure in cancer are summarized. As the presence of gap junctions is relevant in solid tumors, we exemplarily outline their role in glioblastomas and in breast cancer. These were also shown to contain cancer stem cells, which are an essential cause of tumor onset and of tumor transmission into metastases. For these processes, gap junctional communication was shown to be important and thus we summarize, how the expression of gap junction proteins and the resulting communication between cancer stem cells and their surrounding cells contributes to the dissemination of cancer stem cells via blood or lymphatic vessels. Based on their importance for tumors and metastases, future cancer-specific therapies are expected to address gap junction proteins. In turn, gap junctions also seem to contribute to the unattainability of cancer stem cells by certain treatments and might thus contribute to therapeutic resistance.

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Megalencephalic Leukoencephalopathy with Subcortical Cysts Disease-Linked MLC1 Protein Favors Gap-Junction Intercellular Communication by Regulating Connexin 43 Trafficking in Astrocytes

Lanciotti

Brignone

Belfiore

et al. 2020

Cells

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Astrocytes, the most numerous cells of the central nervous system, exert critical functions for brain homeostasis. To this purpose, astrocytes generate a highly interconnected intercellular network allowing rapid exchange of ions and metabolites through gap junctions, adjoined channels composed of hexamers of connexin (Cx) proteins, mainly Cx43. Functional alterations of Cxs and gap junctions have been observed in several neuroinflammatory/neurodegenerative diseases. In the rare leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts (MLC), astrocytes show defective control of ion/fluid exchanges causing brain edema, fluid cysts, and astrocyte/myelin vacuolation. MLC is caused by mutations in MLC1, an astrocyte-specific protein of elusive function, and in GlialCAM, a MLC1 chaperon. Both proteins are highly expressed at perivascular astrocyte end-feet and astrocyte-astrocyte contacts where they interact with zonula occludens-1 (ZO-1) and Cx43 junctional proteins. To investigate the possible role of Cx43 in MLC pathogenesis, we studied Cx43 properties in astrocytoma cells overexpressing wild type (WT) MLC1 or MLC1 carrying pathological mutations. Using biochemical and electrophysiological techniques, we found that WT, but not mutated, MLC1 expression favors intercellular communication by inhibiting extracellular-signal-regulated kinase 1/2 (ERK1/2)-mediated Cx43 phosphorylation and increasing Cx43 gap-junction stability. These data indicate MLC1 regulation of Cx43 in astrocytes and Cx43 involvement in MLC pathogenesis, suggesting potential target pathways for therapeutic interventions.

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Conflicting Roles of Connexin43 in Tumor-Induced Inflammation and Cancer Pathology

Cited by 9 publications

References 98 publications

Connexins in Cancer: Jekyll or Hyde?

Connexins in Cancer: Jekyll or Hyde?

Facets of Communication: Gap Junction Ultrastructure and Function in Cancer Stem Cells and Tumor Cells

Megalencephalic Leukoencephalopathy with Subcortical Cysts Disease-Linked MLC1 Protein Favors Gap-Junction Intercellular Communication by Regulating Connexin 43 Trafficking in Astrocytes

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