Frequent reduction of gap junctional intercellular communication and connexin43 expression in human and mouse lung carcinoma cells

Abstract

The reduced gap junctional intercellular communication (GJIC) and gap junction protein (connexin) expression that have been noted in many neoplastic cell types may contribute to the neoplastic phenotype. We assessed GJIC (by fluorescent dye micro-injection) and connexin expression (by Northern blotting, Western blotting and immunohistochemistry) in five mouse and 17 human lung carcinoma cell lines; both measures were lower in neoplastic cells compared to non-transformed lung epithelial cells. Other connexins were not detected in these cells. Co-culture experiments indicated that carcinoma cell lines able to transfer dye among themselves (homologous GJIC) had little capacity for dye-coupling with non-transformed cells (heterologous GJIC). Southern blot analyses indicated that reductions in GJIC and connexin43 expression were not due to deletions or rearrangements of this gene, but were more likely accounted for by transcriptional down-regulation and/or post-transcriptional factors. No correlations between GJIC and known oncogene and tumor suppressor gene alterations in the human lung carcinoma cells were apparent, suggesting that other mechanisms down-regulate GJIC in these cells. Since the neoplastic cell lines exhibited low GJIC (either homologous or heterologous), this characteristic may be involved in expression of the neoplastic phenotype.

The insulinoma-associated 1: a novel promoter for targeted cancer gene therapy for small-cell lung cancer

“…38,40 The stably expressing HSV-TK and the parental cell lines grow as a suspension cells in vitro and as expected, no 'bystander effect' could be 38 To increase the efficacy of suicide gene therapy for SCLC, it may therefore be beneficial to include an expression system for connexin 43 together with the suicide gene. In addition, several HSV-TK mutants have been generated, which not only increase the sensitivity for GCV many fold, but also increase the 'bystander effect'.…”

“…28,29 In addition to the advantage that GCV is a prodrug already approved for human use, the HSV-TK/GCV system displays 'bystander effects' -both locally and immune mediated. 38,39 Traditionally in vitro assays with suicide genes are performed with virally transduced cell lines, where the suicide gene will be expressed in 100% of the cells with an active promoter. However, using cell lines with relative high transfection efficiencies (approx.…”

A progression-free end-point for idiopathic pulmonary fibrosis trials: lessons from cancer

“…In the lung, Cx43 plays a central role in the regulation of intercellular communications and, although particularly expressed by lung fibroblasts, is considered the major connexin functionally connecting airway, alveolar and endothelial cells [37]. A number of studies have shown a reduced expression of connexins, including Cx43 in some cancers and a subsequent reduction of intercellular communication [38]. The concept of considering both cancer and IPF to share mechanisms closely related to wound healing is also sustained by the involvement of Cx43 in the reparative process that takes place during wound healing.…”

Sharing signals: connecting lung epithelial cells with gap junction channels

“…For instance, tobacco smoke condensates contain substances with the capacity to inhibit gap junctional communication (123,177,183,184,236,237). Cell lines derived from lung tumors are also frequently not coupled through gap junctions, which can be due to a lack of connexin expression or due to constitutively closed gap junction channels (43,233,234). However, not all correlations of changes in connexin expression with tumorigenesis are significant, since reports that Cx37 mutations might be associated with lung cancer (178) were later found to reflect allelic variability in the human Cx37 gene (150).…”