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    Connexin46 in the nucleus of cancer cells: a possible role as transcription modulator
    (Springer Science and Business Media LLC, 2025-03-27)
    Ainoa Fernández-Olivares
    ;
    Viviana P Orellana
    ;
    Jesús Llanquinao
    ;
    NUÑEZ VASQUEZ, GONZALO ESTEBAN  
    ;
    Pablo Pérez-Moreno
    Scopus© Citations 1  10
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    Connexins in Cancer, the Possible Role of Connexin46 as a Cancer Stem Cell-Determining Protein
    (2023)
    Isidora M. León-Fuentes
    ;
    María G. Salgado-Gil
    ;
    María S. Novoa
    ;
    RETAMAL LUCERO, MAURICIO ANTONIO  
    <jats:p>Cancer is a widespread and incurable disease caused by genetic mutations, leading to uncontrolled cell proliferation and metastasis. Connexins (Cx) are transmembrane proteins that facilitate intercellular communication via hemichannels and gap junction channels. Among them, Cx46 is found mostly in the eye lens. However, in pathological conditions, Cx46 has been observed in various types of cancers, such as glioblastoma, melanoma, and breast cancer. It has been demonstrated that elevated Cx46 levels in breast cancer contribute to cellular resistance to hypoxia, and it is an enhancer of cancer aggressiveness supporting a pro-tumoral role. Accordingly, Cx46 is associated with an increase in cancer stem cell phenotype. These cells display radio- and chemoresistance, high proliferative abilities, self-renewal, and differentiation capacities. This review aims to consolidate the knowledge of the relationship between Cx46, its role in forming hemichannels and gap junctions, and its connection with cancer and cancer stem cells.</jats:p>
    Scopus© Citations 3  2
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    Connexin46 Expression Enhances Cancer Stem Cell and Epithelial-to-Mesenchymal Transition Characteristics of Human Breast Cancer MCF-7 Cells
    (2021)
    ACUÑA ASTUDILLO, RODRIGO ANTONIO  
    ;
    Manuel Varas-Godoy
    ;
    Diego Herrera-Sepulveda
    ;
    Mauricio A. Retamal  
    <jats:p>Connexins (Cxs) are a family of proteins that form two different types of ion channels: hemichannels and gap junction channels. These channels participate in cellular communication, enabling them to share information and act as a synchronized syncytium. This cellular communication has been considered a strong tumor suppressor, but it is now recognized that some type of Cxs can be pro-tumorigenic. For example, Cx46 expression is increased in human breast cancer samples and correlates with cancer stem cell (CSC) characteristics in human glioma. Thus, we explored whether Cx46 and glioma cells, can set up CSC and epithelial-to-mesenchymal transition (EMT) properties in a breast cancer cell line. To this end, we transfected MCF-7 cells with Cx46 attached to a green fluorescent protein (Cx46GFP), and we determined how its expression orchestrates both the gene-expression and functional changes associated with CSC and EMT. We observed that Cx46GFP increased Sox2, Nanog, and OCT4 mRNA levels associated with a high capacity to form monoclonal colonies and tumorspheres. Similarly, Cx46GFP increased the mRNA levels of n-cadherin, Vimentin, Snail and Zeb1 to a higher migratory and invasive capacity. Furthermore, Cx46GFP transfected in MCF-7 cells induced the release of higher amounts of VEGF, which promoted angiogenesis in HUVEC cells. We demonstrated for the first time that Cx46 modulates CSC and EMT properties in breast cancer cells and thus could be relevant in the design of future cancer therapies.</jats:p>
      7Scopus© Citations 23
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    Connexin-46 Contained in Extracellular Vesicles Enhance Malignancy Features in Breast Cancer Cells
    (2020)
    ACUÑA ASTUDILLO, RODRIGO ANTONIO  
    ;
    Manuel Varas-Godoy
    ;
    Viviana M. Berthoud
    ;
    ALFARO CORTEZ, IVAN ESTEBAN  
    ;
    RETAMAL LUCERO, MAURICIO ANTONIO  
    <jats:p>Under normal conditions, almost all cell types communicate with their neighboring cells through gap junction channels (GJC), facilitating cellular and tissue homeostasis. A GJC is formed by the interaction of two hemichannels; each one of these hemichannels in turn is formed by six subunits of transmembrane proteins called connexins (Cx). For many years, it was believed that the loss of GJC-mediated intercellular communication was a hallmark in cancer development. However, nowadays this paradigm is changing. The connexin 46 (Cx46), which is almost exclusively expressed in the eye lens, is upregulated in human breast cancer, and is correlated with tumor growth in a Xenograft mouse model. On the other hand, extracellular vesicles (EVs) have an important role in long-distance communication under physiological conditions. In the last decade, EVs also have been recognized as key players in cancer aggressiveness. The aim of this work was to explore the involvement of Cx46 in EV-mediated intercellular communication. Here, we demonstrated for the first time, that Cx46 is contained in EVs released from breast cancer cells overexpressing Cx46 (EVs-Cx46). This EV-Cx46 facilitates the interaction between EVs and the recipient cell resulting in an increase in their migration and invasion properties. Our results suggest that EV-Cx46 could be a marker of cancer malignancy and open the possibility to consider Cx46 as a new therapeutic target in cancer treatment.</jats:p>
      3Scopus© Citations 28
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    Extracellular Cysteines Are Critical to Form Functional Cx46 Hemichannels
    (2022)
    Ainoa Fernández-Olivares
    ;
    Eduardo Durán-Jara
    ;
    Daniel A. Verdugo
    ;
    Mariana C. Fiori
    ;
    Guillermo A. Altenberg
    <jats:p>Connexin (Cxs) hemichannels participate in several physiological and pathological processes, but the molecular mechanisms that control their gating remain elusive. We aimed at determining the role of extracellular cysteines (Cys) in the gating and function of Cx46 hemichannels. We studied Cx46 and mutated all of its extracellular Cys to alanine (Ala) (one at a time) and studied the effects of the Cys mutations on Cx46 expression, localization, and hemichannel activity. Wild-type Cx46 and Cys mutants were expressed at comparable levels, with similar cellular localization. However, functional experiments showed that hemichannels formed by the Cys mutants did not open either in response to membrane depolarization or removal of extracellular divalent cations. Molecular-dynamics simulations showed that Cys mutants may show a possible alteration in the electrostatic potential of the hemichannel pore and an altered disposition of important residues that could contribute to the selectivity and voltage dependency in the hemichannels. Replacement of extracellular Cys resulted in “permanently closed hemichannels”, which is congruent with the inhibition of the Cx46 hemichannel by lipid peroxides, through the oxidation of extracellular Cys. These results point to the modification of extracellular Cys as potential targets for the treatment of Cx46-hemichannel associated pathologies, such as cataracts and cancer, and may shed light into the gating mechanisms of other Cx hemichannels.</jats:p>
      2Scopus© Citations 6
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      17  1Scopus© Citations 12
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      1Scopus© Citations 9  1
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    4-Hydroxynonenal induces Cx46 hemichannel inhibition through its carbonylation
    (2020)
    Mauricio A. Retamal  
    ;
    Mariana C. Fiori
    ;
    Ainoa Fernandez-Olivares
    ;
    Sergio Linsambarth
    ;
    Francisca Peña
    Scopus© Citations 17  5
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    Role and Posttranslational Regulation of Cx46 Hemichannels and Gap Junction Channels in the Eye Lens
    (2022)
    Mauricio A. Retamal  
    ;
    Guillermo A. Altenberg
    <jats:p>Connexins are a family of proteins that can form two distinct types of channels: hemichannels and gap junction channels. Hemichannels are composed of six connexin subunits and when open allow for exchanges between the cytoplasm and the extracellular milieu. Gap junction channels are formed by head-to-head docking of two hemichannels in series, each one from one of two adjacent cells. These channels allow for exchanges between the cytoplasms of contacting cells. The lens is a transparent structure located in the eye that focuses light on the retina. The transparency of the lens depends on its lack of blood irrigation and the absence of organelles in its cells. To survive such complex metabolic scenario, lens cells express Cx43, Cx46 and Cx50, three connexins isoforms that form hemichannels and gap junction channels that allow for metabolic cooperation between lens cells. This review focuses on the roles of Cx46 hemichannels and gap junction channels in the lens under physiological conditions and in the formation of cataracts, with emphasis on the modulation by posttranslational modifications.</jats:p>
      6Scopus© Citations 8
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      8Scopus© Citations 15