Connexins in Cancer: Jekyll or Hyde?

Abstract

The expression, localization, and function of connexins, the protein subunits that comprise gap junctions, are often altered in cancer. In addition to cell–cell coupling through gap junction channels, connexins also form hemichannels that allow communication between the cell and the extracellular space and perform non-junctional intracellular activities. Historically, connexins have been considered tumor suppressors; however, they can also serve tumor-promoting functions in some contexts. Here, we review the literature surrounding connexins in cancer cells in terms of specific connexin functions and propose that connexins function upstream of most, if not all, of the hallmarks of cancer. The development of advanced connexin targeting approaches remains an opportunity for the field to further interrogate the role of connexins in cancer phenotypes, particularly through the use of in vivo models. More specific modulators of connexin function will both help elucidate the functions of connexins in cancer and advance connexin-specific therapies in the clinic.

Applicability of Scrape Loading-Dye Transfer Assay for Non-Genotoxic Carcinogen Testing

“…These two compelling quotes [1,2], separated in time by nearly two decades of extensive research in the field of cancer, nicely sum up the motivation and rationale for this review paper. Here, we systematically searched currently available data on the ability of chemical substances to disrupt gap junctional intercellular communication (GJIC), as they were acquired by one of the most frequently used in vitro assays for this purpose, i.e., the scrape-loading-dye transfer (SL-DT) technique.…”

“…"Here, we review the literature surrounding connexins in cancer cells in terms of specific connexin functions and propose that connexins function up stream of most, if not all, of the hallmarks of cancer" [2].…”

“…Chemical carcinogens can be classified into three main groups [16,17]: (1) ultimate carcinogens (chemicals with a direct action with the capacity to induce cancer without a previous metabolic activation), (2) procarcinogens (chemicals that need to be activated by metabolic activation to become ultimate carcinogens) and (3) co-carcinogens (chemical substances that cannot induce cancer when administered alone but can enhance the carcinogenic effect of other substances). From a toxicological and regulatory perspective, chemical carcinogens can be classified according to their prevailing mechanism as genotoxic carcinogens (GTxC), which include mutagenic or genotoxic agents inducing mutations and DNA damage by "errors of DNA repair" during initiation and eventually also progression stage.…”

Connexins, Innexins, and Pannexins: From Biology to Clinical Targets

“…One of the most multifactorial diseases is cancer. Connexins regulate all of the hallmarks of cancer, but in a complex manner, bestowing both pro-and anti-tumorigenic properties through the action of gap junctions, hemichannels, and non-junctional proper-ties, as reviewed in this SI by Mulkearns-Hubert et al [15]. While summarizing all of these hallmarks, the authors reiterate the need for progress in connexin-modulating approaches to help in elucidating functions and developing specific clinical therapies.…”

“…While summarizing all of these hallmarks, the authors reiterate the need for progress in connexin-modulating approaches to help in elucidating functions and developing specific clinical therapies. The "Jekyll and Hyde" role for connexins in cancer is highlighted [15] and is an obvious challenge. Most cancer-related studies concern Cx43, for which this dichotomous role is prominent.…”