Connexin-26 Is a Key Factor Mediating Gemcitabine Bystander Effect

Abstract

Gemcitabine is a nucleoside analogue with anticancer activity. Inside the cell, it is sequentially phosphorylated to generate the active drug. Phosphorylated nucleoside analogues have been shown to traffic through gap junctions. We investigated the participation of gap junctional intercellular communication (GJIC) as a possible mechanism spreading gemcitabine cytotoxicity in pancreatic tumors. Immunohistochemical analysis of pancreatic cancer biopsies revealed increased connexin 26 (Cx26) content but loss of connexins 32 (Cx32) and 43 (Cx43) expression. Cx26 abundance in neoplastic areas was confirmed by Cx26 mRNA in situ hybridization. Heterogeneity on the expression levels and the localization of Cx26, Cx32, and Cx43 were identified in pancreatic cancer cells and found to be associated with the extent of GJIC, and correlated with gemcitabine bystander cytotoxic effect. The abundance of Cx26 at the contact points in tumoral regions prompted us to study the involvement of Cx26 in the GJIC of gemcitabine toxic metabolites and their influence on the antitumoral effects of gemcitabine. Knockdown of Cx26 led to decreased GJIC and reduced gemcitabine bystander killing whereas overexpression of Cx26 triggered increased GJIC and enhanced the gemcitabine cytotoxic bystander effect. Gemcitabine treatment of mice bearing tumors, with a high GJIC capacity, resulted in a significant delay in tumor progression. Interestingly, gemcitabine administration in mice bearing tumors that overexpress Cx26 triggered a dramatic tumor regression of 50% from the initial volume. This study shows that Cx26 participates in the gap junction-mediated bystander cytoxic effect of gemcitabine and provides evidence that upregulation of Cx26 improves gemcitabine anticancer efficacy. Mol Cancer Ther; 10(3); 505-17. Ó2011 AACR.

Changes in Connexin43 Expression and Localization During Pancreatic Cancer Progression

“…It may be that the changes we see in Cx43 expression over time are associated with specific lesions or stages of PDA; to examine this idea a rigorous histological analysis of Cx43 localization is presently underway. Previous studies have indicated that Cx26 is overexpressed in human pancreatic cancer (Garcia-Rodriguez et al 2011; Kyo et al 2008). It will be interesting to confirm that this occurs in the mouse model and to compare the Cx26 expression profile to what we see with Cx43.…”

Homo sapiens Systemic RNA Interference-defective-1 Transmembrane Family Member 1 (SIDT1) Protein Mediates Contact-dependent Small RNA Transfer and MicroRNA-21-driven Chemoresistance

“…GJIC can increase the susceptibility of cancer cells to cytotoxic agents through connexin-mediated "bystander effects" in pancreatic cancer (56). BxPC3 cells in which GJIC is artificially increased exhibit bystander cytotoxicity when exposed to gemcitabine (56 -58).…”

Tanshinone IIA Increases the Bystander Effect of Herpes Simplex Virus Thymidine Kinase/Ganciclovir Gene Therapy via Enhanced Gap Junctional Intercellular Communication

“…Transfection or transduction of Cx26 and Cx43 results in increased GJIC, and consequently leads to an increased bystander effect seen in suicide gene therapy [7], [19]. Alternatively, a number of classes of chemicals, including gemcitabine [20], cAMP [21], and retinoids [22], have been reported to increase Cx26 and Cx43 and, subsequently, GJIC.…”