Opposing roles of connexin43 in glioma progression

Abstract

Despite the tremendous amount of data over the last 40years, lack of gap junctional intercellular communication (GJIC) or altered expression of gap junction proteins is still a lesser known 'hallmark' of cancer. Expression of astrocytic gap junction protein, connexin43 (Cx43), is often reduced in astrocytomas, the most common neoplasia of the central nervous system (CNS) in adults. Supported by a number of evidences, the global decrease of Cx43 expression appears to be advantageous for the growth of glioma cells. Although the mechanisms by which Cx43 regulates the expression levels of proteins involved in cell growth is unclear, there are evidences to suggest that it might be independent of their channel forming properties. In this regard, the carboxyl tail of Cx43 may have the ability to control the translocation of transcription factor regulators into the nucleus. However, this putative tumor suppressor effect of Cx43 is counterbalanced by its capacity to enhance the migration of glioma cells out of the tumor core through mechanisms that seems to implicate its carboxyl tail, possibly by interacting with the actin cytoskeleton. This ambivalence between the tumor suppressor effect and promotion of cell migration may partly be explained by the heterogeneous expression of Cx43 in the glioma core especially at the malignant glioblastoma stage; some tumor cells would be expected to migrate (Cx43 expressing cells) and others to proliferate (non-expressing Cx43 cells). Moreover, the involvement of Cx43 in glioma progression seems to be more complex since, in addition, GJIC may increase their resistance to apoptosis and Cx43 may also affect cell homeostasis in a paracrine fashion via hemichannel action. In conclusion, Cx43 appears to be involved at different levels of the glioma progression by acting on cell growth regulation, promotion of cell migration and resistance to apoptosis. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.

Connexin43 confers Temozolomide resistance in human glioma cells by modulating the mitochondrial apoptosis pathway

“…Therefore, introduction of oncogenes and mitogens to cultured cells interfere with GJIC by reducing the number of connexin-containing GJ plaques and/or alter its trafficking to the plasma membrane (Laird et al, 1995;Naus and Laird, 2010). The role of Cx43 in apoptosis is less well studied and it remains controversial whether GJIC is pro-or anti-apoptotic (Sin et al, 2012). Recent evidence suggests the hemichannel activity of Cx43 may have a more significant role than intercellular channel activity in affecting cell death Decrock et al, 2009;Retamal et al, 2006), and identification of Cx43 in mitochondria suggests GJ proteins may influence pathways linked to apoptosis control (Lu et al, 2010;Ruiz-Meana et al, 2008).…”

“…Various studies in gliomas have demonstrated a role of Cx43 in glioma growth control and migration [reviewed in (Sin et al, 2012)]. The reduction of GJIC in tumor cells is often attributed to reduced Cx43 expression (Mesnil et al, 2005).…”

Expression of a gap junction protein, connexin43, in a large panel of human gliomas: new insights

“…Moreover, it does not help for a better characterization of glioblastomas. The fact that Cx43 is still detected in high‐grade gliomas (grades III and IV) may be in favor of the presence of possibly invasive cells as glioblastoma are known to be very invasive and Cx43 has been involved in vitro in glioma migration and invasion 21, 22. Future in situ studies will determine whether Cx43 is related to in situ glioma invasion even for low‐grade tumors.…”

Density-Dependent Regulation of Glioma Cell Proliferation and Invasion Mediated by miR-9

“…Adjacent glioma cells physically interact via adhesion proteins, microtubes, membrane fusing, microvesicles, and by gap junctions [34][35][36][37]. Although the mechanisms by which adjacent tumor cells interact are numerous, substantial evidence indicates that gap junctions play key roles in intercellular communication, and can regulate both glioma proliferation and invasion [36,[38][39][40]. Indeed, even cell-to-cell interactions via microtubes, adherens, and microvesicles are modulated by gap junctions [34,41,42].…”