The pro- and anti-tumoral properties of gap junctions in cancer and their role in therapeutic strategies

Abstract

Gap junctions (GJs), essential structures for cell-cell communication, are made of two hemichannels (commonly called connexons), one on each adjacent cell. Found in almost all cells, GJs play a pivotal role in many physiological and cellular processes, and have even been linked to the progression of diseases, such as cancer. Modulation of GJs is under investigation as a therapeutic strategy to kill tumor cells. Furthermore, GJs have also been studied for their key role in activating anti-cancer immunity and propagating radiation- and oxidative stress-induced cell death to neighboring cells, a process known as the bystander effect. While, gap junction (GJ)-based therapeutic strategies are being developed, one major challenge has been the paradoxical role of GJs in both tumor progression and suppression, based on GJ composition, cancer factors, and tumoral context. Therefore, understanding the mechanisms of action, regulation, and the dual characteristics of GJs in cancer is critical for developing effective therapeutics. In this review, we provide an overview of the current understanding of GJs structure, function, and paradoxical pro- and anti-tumoral role in cancer. We also discuss the treatment strategies to target these GJs properties for anti-cancer responses, via modulation of GJ function.

Keywords: Anti-cancer immunity; Bystander effect; Gap junctions; Oxidative stress.

Graphical representation of the pro- and anti-tumorigenic properties of gap junction proteins in cancer cells.

Fig. 1

Schematic representation of GJs and effector functions between different cell types. GJs are key mediators of intercellular communication. Moreover, a previously underestimated role of GJs in alternative pathways for immune regulation and activation has been recently described (see section 6 for explanation). (A) Tumor cell transfers tumor promoting signals to another tumor cell via homologous GJs, increasing tumoral effects. Besides, homologous GJs also transfer death signals (Ca²⁺) between tumor cells, inducing tumor cell death. (B) Tumor cell transfers Ag peptides to DC via GJs, leading to antigen cross-presentation by DC. Further, DC presents Ag peptides and transfers secondary messengers to CD8⁺ T cell and NK cell, respectively, killing target cells by cytotoxic lymphocytes. (C) Metastatic tumor cell transfers Ca²⁺ and cGAMP to astrocyte via heterologous GJs, inducing further tumor spreading and therapy resistance. (D) NK cell transfers Ca²⁺ to tumor cells via Cx43 GJs, for induction of GrzmB-mediated cell death. A rise in the intracellular Ca²⁺ concentration in the target cell is needed for efficient killing by cytotoxic T lymphocytes or NK cells.

Fig. 2

Schematic representation of a Cx43 protein in a lipid bilayer membrane. (A) The transmembrane domains TM1, TM2, TM3, and TM4 are represented in blue, red, orange and yellow colors, respectively. (B) The extracellular (EL-1 and EL-2) and cytoplasmic (CL) loops are represented in pink, black, and purple colors, respectively. The amino (NT) and carboxyl (CT) terminus are represented in green and gray colors, respectively. For the sake of clarity, only a small part of the CT domain is represented. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

Representations of the 3D structure of Cx26 proteins-composed connexons. The Cx26 structure can be obtained from the Protein Data Bank website (https://www.rcsb.org/) (accession no. 2ZW3). Side view (on the left) and top view (on the right). (A) Each color represents a Cx monomer. (B) Homomeric connexon. (C) Heteromeric connexon. (D) Schematic representation of GJIC (or only GJ) between Cx46 proteins-composed connexons (4 possibilities are shown). The Cx46 structure can be obtained from the Protein Data Bank website (https://www.rcsb.org/) (accession no. 6MHQ). Exchange of possible types of ions, amino acids, secondary messengers, cancer-associated signaling molecules, nutrients and microRNAs between two cells is illustrated as geometrical shapes of different colors. For simplicity only a few examples for each class are shown. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 4

Factors influencing the tumor-promoting and tumor-suppressing properties of Cxs and GJs.

Fig. 5

Schematic representation of the effects of RONS-induced oxidative stress on GJs and connexons. (1) GJs are able to transport RONS between cells. (2) RONS induce connexon opening to allow the entry of RONS to the cell interior. (3) Proposed mechanism to increase the intracellular RONS accumulation: Connexon blockers induce connexon close state and increase the intracellular accumulation of RONS, by entrance of them through the membrane and by natural intracellular production (e.g., within the mitochondria and cytoplasm). Taken together, these events induce cell death.