Connexins-Therapeutic Targets in Cancers

Abstract

Connexins (Cx) are members of a protein family that forms intercellular channels localised in gap junction (GJ) plaques and single transmembrane channels called hemichannels. They participate in intercellular communication or communication between the intracellular and extracellular environments. Connexins affect cell homeostasis, growth and differentiation by enabling the exchange of metabolites or by interfering with various signalling pathways. Alterations in the functionality and the expression of connexins have been linked to the occurrence of many diseases. Connexins have been already linked to cancers, cardiac and brain disorders, chronic lung and kidney conditions and wound healing processes. Connexins have been shown either to suppress cancer tumour growth or to increase tumorigenicity by promoting cancer cell growth, migration and invasiveness. A better understanding of the complexity of cancer biology related to connexins and intercellular communication could result in the design of novel therapeutic strategies. The modulation of connexin expression may be an effective therapeutic approach in some types of cancers. Therefore, one important challenge is the search for mechanisms and new drugs, selectively modulating the expression of various connexin isoforms. We performed a systematic literature search up to February 2020 in the electronic databases PubMed and EMBASE. Our search terms were as follows: connexins, hemichannels, cancer and cancer treatment. This review aims to provide information about the role of connexins and gap junctions in cancer, as well as to discuss possible therapeutic options that are currently being studied.

Keywords: cancer; cancer treatment; connexin; gap junction; hemichannel; intercellular communication.

Figure 1

Connexin–protein interactions influencing carcinogenesis. (a) The binding of Cx43 to cytoskeleton proteins tubulin, cadherins, catenins, vinculin, ZO-1 and drebrin regulates cell migration and metastasis. Cx43 inhibits the connection of Smad2/3 with tubulin, causing the secretion of Smad2/3, which regulates pathways associated with TGF-β. TGF-β signalling plays an important role in many cancers such breast, colon, lung, pancreatic and prostate cancer. Cx43 enhances c-Src blockade, and by a connection with c-Src as well as CSK and PTEN, which are c-Src endogenous inhibitors. C-Src tyrosine kinase is a proto-oncogene involved in many cellular pathways such as cell migration, proliferation and survival. The dysregulation of c-Src leads to malignant transformation and has been observed in several cancer types. C-Src tyrosine kinase also plays an important role in resistance to chemotherapy. Cx43 inhibits in the nucleus the transcriptional activity of β-catenin, drebrin, ezrin and ZO-1 regulating the expression of genes controlling the process of carcinogenesis. (b) Cx26 plays an important role in maintenance of the cancer stem cell (CSC) phenotype in triple-negative breast cancer. Cx26 enhances CSC self-renewal by interaction with the pluripotency transcription factor NANOG and focal adhesion kinase (FAK). (c) Cx50 regulates the expression of the cyclin-dependent kinase inhibitor p27/p57 and E3 ubiquitin ligase Skp2. Cx50 enhances auto-ubiquitination and subsequent degradation of Skp2. Through this mechanism, Cx50 regulates the expression of mediators regulating cell growth and differentiation [17].

Figure 2

Connexin synthesis steps as therapeutic targets. (a) Transcription: Histone acetylation: histone acetyltransferase enzymes (HATs), histone deacetylases (HDACs); Transcription factors: Runx1, Ap-1, Sp-1, β-catenin, TCF/LEF; Promoter hypermethylation: DNA methyltransferase enzymes (DNMTs). (b) mRNA translational regulation: microRNA replacement; microRNA antagonists; Internal translation: mTOR and Mnk1/2; GJA1-20k (truncated forms of Cx43): Smad3/ERK-dependent repression of GJA1-20k reduces Cx43 gap junctions. (c) Post-translational regulation: Phosphorylation: mitogen-activated protein kinase (MAPK), protein kinase C (PKC), protein kinase A (PKA), cdc2/cyclin B and v-Src/c-Src; Acetylation; Ubiquitination; SUMOylation [17].