DEFECTIVE GAP JUNCTIONAL INTERCELLULAR COMMUNICATION IN LUNG CANCER: Loss of an Important Mediator of Tissue Homeostasis and Phenotypic Regulation

Abstract

Gap junctions provide direct pathways for the exchange of molecules and ions between neighboring cells, a process known as gap junctional intercellular communication (GJIC). This GJIC is important for homeostasis and regulation of mitosis, differentiation, and apoptosis. Gap junctions are present in lung airway and alveolar epithelial cells and, in addition to the above roles, might coordinate ciliary beating and surfactant secretion. GJIC is decreased in human and mouse lung carcinoma cells because of reduced expression of the gap junction protein, connexin43 (Cx43), and defects in signal transduction pathways that mediate Cx43 function. This reduced GJIC is important in the behavior of lung carcinoma cells because forced expression of Cx43 in lung carcinoma cells inhibits their growth and tumorigenicity. In this report, we summarize our studies on the role of GJIC in lung neoplasia.

Iodide sensitizes genetically modified non-small cell lung cancer cells to ionizing radiation

“…30,31 Studies have shown that GJIC may progressively decrease during multistage carcinogenesis. 21 Interestingly, a low iodine diet inhibits GJIC in thyroid follicular cells. 32 In the current study, we tested whether GJIC might play a role in iodide-induced bystander tumoricidal effect by the double-dye transfer assays.…”

“…21 A decrease in GJIC activity has been documented in many human malignancies including lung cancer. 21 This may be a consequence of reduced expression of Cx43 and defects in signal transduction pathways that mediate Cx43 function.…”

“…21 A decrease in GJIC activity has been documented in many human malignancies including lung cancer. 21 This may be a consequence of reduced expression of Cx43 and defects in signal transduction pathways that mediate Cx43 function. 21 To test whether iodideinduced GJIC activity in the NIS/TPO-modified NSCLC correlates with an increase in Cx43, H1299NT1 and H1299Ctr cells were incubated in medium alone or in medium containing 30 mM KI for 24 h. Cell lysates of each Iodide sensitizes NSCLC cells to radiation L Zhang et al condition were applied to Western blot analysis using specific monoclonal anti-Cx43 antibody.…”

Sharing signals: connecting lung epithelial cells with gap junction channels

“…Also, forced connexin expression can sometimes reduce the tumor-forming capacity of some cell lines (101,233). There may be a role for connexin specificity here, since Cx32 suppressed the tumorforming capacity of a lung carcinoma cell line (234), although Cx43, but not Cx32, conferred growth control to a glioma cell line (101). As a further complication to understanding roles for gap junctions in carcinogenesis, heterocellular communication between tumor cells and endothelial cells appears to be required for transmigration (135).…”

“…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).…”