Connexins as targets for cancer chemoprevention and chemotherapy

Abstract

Cells within a tissue continuously interact to coordinate normal tissue functions and maintain homeostasis. Gap junctional communication (GJC), mediated by the connexin protein family, allows this type of intercellular crosstalk resulting in synchronized and cooperative tissue behavior such as cardiac contraction. In cancer, loss of these types of cell:cell interactions has been shown to facilitate tumorigenesis and enable the autonomous cell behavior associated with transformed cells. Indeed, many human tumor lines demonstrate deficient or aberrant GJC and/or loss of connexin expression. Restoration of exogenous connexin expression/GJC function is correlated with increased cell growth control both in vitro and in vivo. In support of this growth regulatory hypothesis, decreased connexin expression has been observed in situ in early human neoplasia of various organs. Additionally, genetically engineered mice lacking particular connexins (Connexins 32 or 43) exhibit increased susceptibility to radiation and chemically-induced liver and/or lung tumorigenesis. These studies strongly suggest that connexins and GJC serve a tumor suppressor role. Consistent with this proposed role, in a model cell culture system, retinoids and carotenoids up-regulate Connexin43 (Cx43) expression in direct proportion to their ability to suppress carcinogen-induced neoplastic transformation. Here, we discuss the important role of connexins and GJC in tumorigenesis and suggest the possibility of connexins as potential anti-oncogenic targets for chemoprevention and/or chemotherapy.

Connexin43 pseudogene in breast cancer cells offers a novel therapeutic target

“…This also suggests a potential therapeutic strategy to enhance Cx43 and sensitize cancer cells to cytotoxic chemotherapy. The expression of Cx43 in gap junction-deficient tumor cell lines has been well documented as a means of reestablishing several aspects of growth control (43). More recently, it has been shown that increased Cx43 enhances chemosensitivity in several cancer models (24,25).…”

Medicinal Potentials and Toxicity Concerns of Bioactive Principles

“…In another study, quercetin, the active phenolic component in kiwifruit, mediated by its free radical-scavenging activity, prevented hydrogen peroxideinduced inhibition of gap-junction intercellular communication in rat liver epithelial cells that is required for cell-cell communication in order to maintain homeostasis by facilitating direct exchanges of essential cellular metabolites and messengers less than 1-2 kDa (e.g. , cyclic AMP and ATP) [165][166][167]. Additionally, quercetin possesses chemopreventive activity against azoxymethane-induced colonic tumorigenesis in mice and pre-neoplastic lesions in rat hepatocarcinogenesis [167].…”

Connexins and Cadherin Cross-talk in the Pathogenesis of Prostate Cancer

“…Moreover, many studies have shown that over-expression of Cxs in tumor cells attenuates the malignant phenotype in vivo and in vitro, reverses the changes associated with epithelial to mesenchymal transformation (EMT), and induces differentiation [3;4;6]. For example, Cx32 is expressed in the liver, lung, and exocrine glands, and knock out studies have shown that the incidence of carcinogen-induced tumors in these mice is higher [7][8][9]. Moreover, mutations in several Cx genes have been characterized in inherited diseases associated with aberrant proliferation and differentiation [1;10].…”