Connexins and Glucose Metabolism in Cancer

Abstract

Connexins are a family of transmembrane proteins that regulate diverse cellular functions. Originally characterized for their ability to mediate direct intercellular communication through the formation of highly regulated membrane channels, their functions have been extended to the exchange of molecules with the extracellular environment, and the ability to modulate numerous channel-independent effects on processes such as motility and survival. Notably, connexins have been implicated in cancer biology for their context-dependent roles that can both promote or suppress cancer cell function. Moreover, connexins are able to mediate many aspects of cellular metabolism including the intercellular coupling of nutrients and signaling molecules. During cancer progression, changes to substrate utilization occur to support energy production and biomass accumulation. This results in metabolic plasticity that promotes cell survival and proliferation, and can impact therapeutic resistance. Significant progress has been made in our understanding of connexin and cancer biology, however, delineating the roles these multi-faceted proteins play in metabolic adaptation of cancer cells is just beginning. Glucose represents a major carbon substrate for energy production, nucleotide synthesis, carbohydrate modifications and generation of biosynthetic intermediates. While cancer cells often exhibit a dependence on glycolytic metabolism for survival, cellular reprogramming of metabolic pathways is common when blood perfusion is limited in growing tumors. These metabolic changes drive aggressive phenotypes through the acquisition of functional traits. Connections between glucose metabolism and connexin function in cancer cells and the surrounding stroma are now apparent, however much remains to be discovered regarding these relationships. This review discusses the existing evidence in this area and highlights directions for continued investigation.

Keywords: connexin; gap junction; glucose; metabolism.

Figure 1

Canonical role of connexins in gap junctional intercellular communication. (A) Connexin proteins contain four transmembrane domains (TD), intracellular facing N- and C-terminal regions, two extracellular loops (EL) and one cytoplasmic loop (CL). C-terminal tail and CL are sites of post-translational modifications that affect many aspects of connexin biology. Six connexins form a hexameric channel known as a connexon which forms a highly regulated aqueous pore. (B) Connexons are inserted into the plasma membrane and connexons on opposing cell membranes connect to form a gap junction, capable of direct transfer of small molecules and ions. Interactions between ELs are important for formation of gap junctions while other domains mediate different aspects of channel permeability and gating properties. (C) Connexons composed of a single type of connexin are termed homomeric while connexons formed from multiple connexins are heteromeric. Gap junctions formed between the same homomeric channels are termed homotypic while connexon docking of differing homomeric channels, or between heteromeric channels are termed heterotypic. The multitude of permutations of these combinations affect the type and directionality of substrate transfer between cells.

Figure 2

Role of gap junctions during cancer progression. (A) GJIC is an essential part of cellular and tissue homeostasis in healthy cells. (B) During tumor initiation, loss of GJIC in cancer cells and downregulation of connexin expression is commonly observed. However, the functions of connexins and gap junctions can suppress or facilitate tumor growth. (C) During the multi-step process of metastasis, GJIC has been shown to facilitate interactions with other cells (e.g., endothelial cells) to promote the steps of the metastatic cascade. (D) Upon reaching a secondary site, adaptation to a new microenvironment must occur and evidence has shown that GJIC between metastatic cells and stromal cells of these sites can promote survival and outgrowth, completing the process of metastasis.

Figure 3

Examples of relationships between glucose availability, metabolism and connexin function. (A) Gap junctions allow for exchange of metabolites with a tumor. As tumors grow, regions of hypoxia develop depending on tumor vasculature and angiogenesis. Active GJIC allows for the transfer of glucose and bicarbonate from perfused regions to hypoxic areas. Additionally, metabolites such as lactate can be shuttled to normoxic areas for utilization and reduced buildup, collectively normalizing metabolism in the absence of an integrated blood supply, Refs. [156,157,158]. (B) In a process referred to as the reverse Warburg effect, cancer cells induce glycolytic metabolism in stromal cells such as cancer associated fibroblasts (CAFs). This in turn leads to stimulation of oxidative metabolism in cancer cells through the transfer of metabolites. In some models this effect has been shown to be dependent on unidirectional transfer through GJIC, Ref. [162]. (C) Connexin expression has been shown capable of controlling metabolic enzymes within cancer cells that affect glycolysis. Although much remains to be determined, many of these effects are mediated through channel-independent functions of connexins. Metabolic reprogramming, or inhibition of this process, affects the adaptability of cancer cells to metabolic changes in the microenvironment, Refs. [179,180,181]. (D) Adaptation to reduced glucose availability can lead to increased connexin expression, membrane localization and GJIC with associated increases in phenotypic qualities such as survival and invasion, Refs. [224,225]. Abbreviations: Glu, glucose; HCO₃⁻, bicarbonate; Lac, lactate; CAC, citric acid cycle. References correspond to related material discussed in this article.

Figure 4

Emerging connections between connexin regulation and glucose metabolism. Data for some relationships is limited in cancer and requires continued research to better define the significance of these associations, which are likely to exhibit interdependence.