Gap junction intercellular communication propagates cell death in cancerous cells

• Published in: Oncogene Vol. 21; no. 13; pp. 1989 - 1999
• Main Authors: KRUTOVSKIKH, Vladimir A, PICCOLI, Colette, YAMASAKI, Horashi
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 21.03.2002; Nature Publishing Group
• Subjects: Ageing, cell death; Animals; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Bladder cancer; Blotting, Western; Calcium permeability; Cancer cells; Cell Adhesion; Cell Communication; Cell death; Cell interaction; Cell interactions; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cellular signal transduction; Connexin 43; Connexin 43 - genetics; Connexin 43 - metabolism; DNA - analysis; Fundamental and applied biological sciences. Psychology; Gap junctions; Gap Junctions - metabolism; Genetic aspects; Glycyrrhetinic Acid - pharmacology; Homeostasis; Microscopy, Fluorescence; Molecular and cellular biology; Mutation; Oleamide; Oleic Acids - pharmacology; Physiological aspects; Rats; Signal Transduction - drug effects; Time Factors; Tumor Cells, Cultured; Urinary Bladder Neoplasms - metabolism; Urinary Bladder Neoplasms - pathology; France; Japan; Carcinoma; Rat; Transformed cell; Rodentia; Malignant tumor; Gap junction; Connexin; Vertebrata; Mammalia; Cell line; Cell death; Bladder disease; Onc gene; Apoptosis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1205187

Gap junction intercellular communication (GJIC) or cell coupling has an important function in maintaining tissue homeostasis and is thus a critical factor in the life and death balance of cells. While the role of GJIC in cell growth regulation has been much studied, its involvement in apoptosis remains unclear. In this study we elucidated the possibility that cell death is propagated via gap junctions, employing the rat bladder carcinoma cell line BC31. BC31 cells proliferate quickly, are tumorigenic, and are well-coupled via gap junctions that contain the gap junction protein Connexin43 (Cx43). In addition, these cells are predisposed to spontaneous death by apoptosis, particularly upon achieving confluency. We found that many dying BC31 cells express Cx43 just as their non-apoptotic counterparts do. Furthermore, Cx43 in apoptotic cells could be functionally competent, supporting coupling of these cells with their non-apoptotic neighbors, and as a result, clusters of coordinately dying cells were observed. The role of Cx43 and GJIC in propagating cell death was shown by analysing clones of BC31 cells expressing a mutant of Cx43 that is a dominant negative inhibitor of GJIC, and by using beta-glycyrrhetinic acid to inhibit intrinsic cell coupling in BC31 cells: in both cases the formation of clusters of dying cells was abrogated, and the intensity of cell death was considerably decreased. These results suggest that GJIC spreads cell-killing signals initially generated by a single cell that spontaneously initiates apoptosis, into healthy surrounding cells, thus increasing the level of cell death. Treatment of BC31 cells with the sleep-inducing lipid Oleamide, which selectively restricts gap junction permeability to Ca(2+) ions, did not abrogate coordinated cell death by clusters, indicating that Ca(2+) ions are the most probable cell-killing signals spread through gap junctions.