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Gap junctional communication and neoplastic transformation
A Hotz-Wagenblatt1, D Shalloway
1Department of Pathology, Cornell University, Ithaca, NY 14853.
Abstract:
Gap junctional communication (GJC) is mediated by channels consisting of connexins and can be differentially regulated by ions, second messengers, kinases, phosphatases, and cell adhesion molecules. Tumor cells and oncogene-transformed cells often, but not always, show reduced homologous GJC between themselves. A more stringent correlation may exist between transformation and reduced heterologous communication between transformed cells and normal neighbors. Reduced GJC seems to stimulate tumor promotion but has no significant effect on the initiation phase of carcinogenesis. These effects may reflect the importance of intercellular passage of second messengers or other small molecules in cell growth control. Some evidence suggests that gap junction in combination with cell adhesion molecules can affect metastatic potential, but a clear picture has not yet emerged. Coupling and gap junction expression can be regulated both pre- and posttranslationally in oncogene-transformed cells. Src probably downregulates GJC in fibroblasts by tyrosine phosphorylation of connexin43. The Ras-induced reduction in GJC appears to be caused by decreased connexin expression. E1A, but not Myc and Fos, downregulates GJC to some extent. Artificial expression of connexin in glioma, hepatoma, chemically transformed, and src-transformed cells can restore GJC and suppress growth and/or tumorigenesis. These results argue for involvement of GJC in transformation and growth control.
Insights
Reduced gap junctional communication (GJC) in tumor cells correlates with tumor promotion, not initiation. Restoring GJC can suppress cancer growth and tumorigenesis, highlighting its role in cell growth control.
Area of Science:
- Cell Biology
- Cancer Research
- Molecular Biology
Background:
- Gap junctional communication (GJC) is vital for cell-to-cell signaling, mediated by connexin channels.
- Tumorigenesis is often associated with altered GJC, particularly reduced communication between normal and transformed cells.
- The precise role of GJC in cancer initiation versus promotion requires further elucidation.
Purpose of the Study:
- To investigate the correlation between altered gap junctional communication and cancer development.
- To explore the mechanisms by which oncogenes affect GJC.
- To assess the therapeutic potential of restoring GJC in cancer cells.
Main Methods:
- Analysis of GJC in various tumor cell lines and oncogene-transformed cells.
- Investigating the impact of specific oncogenes (Src, Ras, E1A) on connexin expression and function.
- Assessing the effects of artificially restoring connexin expression on cell growth and tumorigenesis.
Main Results:
- Reduced homologous and heterologous GJC is frequently observed in transformed cells, potentially stimulating tumor promotion.
- Specific oncogenes like Src and Ras downregulate GJC through distinct mechanisms (tyrosine phosphorylation, decreased expression).
- Restoring GJC by artificial connexin expression suppressed growth and tumorigenesis in multiple cancer models.
Conclusions:
- Altered GJC is implicated in cancer development, particularly in tumor promotion and progression.
- Intercellular communication via gap junctions plays a significant role in regulating cell growth and controlling tumorigenesis.
- Restoring functional gap junctions represents a potential therapeutic strategy for cancer treatment.