Abstract
Dysregulation of gap junctional intercellular communication (GJIC) has been associated with different pathologies, including cancer; however, molecular mechanisms regulating GJIC are not fully understood. Mitogen Activated Protein Kinase (MAPK)-dependent mechanisms of GJIC-dysregulation have been well-established, however recent discoveries have implicated phosphatidylcholine-specific phospholipase C (PC-PLC) in the regulation of GJIC. What is not known is how prevalent these two signaling mechanisms are in toxicant/toxin-induced dysregulation of GJIC, and do toxicants/toxins work through either signaling mechanisms or both, or through alternative signaling mechanisms. Different chemical toxicants were used to assess whether they dysregulate GJIC via MEK or PC-PLC, or both Mek and PC-PLC, or through other signaling pathways, using a pluripotent rat liver epithelial oval-cell line, WB-F344. Epidermal growth factor, 12-O-tetradecanoylphorbol-13-acetate, thrombin receptor activating peptide-6 and lindane regulated GJIC through a MEK1/2-dependent mechanism that was independent of PC-PLC; whereas PAHs, DDT, PCB 153, dicumylperoxide and perfluorodecanoic acid inhibited GJIC through PC-PLC independent of Mek. Dysregulation of GJIC by perfluorooctanoic acid and R59022 required both MEK1/2 and PC-PLC; while benzoylperoxide, arachidonic acid, 18β-glycyrrhetinic acid, perfluorooctane sulfonic acid, 1-monolaurin, pentachlorophenol and alachlor required neither MEK1/2 nor PC-PLC. Resveratrol prevented dysregulation of GJIC by toxicants that acted either through MEK1/2 or PC-PLC. Except for alachlor, resveratrol did not prevent dysregulation of GJIC by toxicants that worked through PC-PLC-independent and MEK1/2-independent pathways, which indicated at least two other, yet unidentified, pathways that are involved in the regulation of GJIC. In conclusion: the dysregulation of GJIC is a contributing factor to the cancer process; however the underlying mechanisms by which gap junction channels are closed by toxicants vary. Thus, accurate assessments of risk posed by toxic agents, and the role of dietary phytochemicals play in preventing or reversing the effects of these agents must take into account the specific mechanisms involved in the cancer process.
Highlights
Gap junctional intercellular communication (GJIC) represents a key regulatory mechanism for the maintenance of tissue homeostasis, regulation of cell growth, differentiation and death [1,2]
GJIC was measured by scalpel loading-dye transfer (SL-DT) bioassay in a WB-F344 rat liver epithelial cells pre-incubated with an inhibitor of phosphatidylcholine-specific phospholipase C (PC-PLC) or MEK1/2, or resveratrol, followed by the addition of a GJIC-dysregulating chemical
Toxicants whose effects on GJIC were significantly attenuated by a PC-PLC inhibitor, D609, but not by MEK1/2 inhibitor, were fluorene, 1-methylfluorene, fluoranthene, phenanthrene, 1-methylanthracene, 9,10-dimethylanthracene, pyrene, 1-methylpyrene, perfluorodecanoic acid (PFDA), dicumylperoxide, PCB-153 and DDT (Fig 2A and 2B)
Summary
Gap junctional intercellular communication (GJIC) represents a key regulatory mechanism for the maintenance of tissue homeostasis, regulation of cell growth, differentiation and death [1,2]. Chronic impairment of GJIC caused by oncogene activation, endogenous cell-death-induced compensatory release of growth factors or by exposure to tumorigenic xenobiotics is strongly linked to the promoting phase of cancer [5,6]. A number of chemicals are known to rapidly dysregulate GJIC, including a model tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA), biological toxins, organic solvents, environmental pollutants, pesticides, pharmaceuticals, peroxides, metals and others [9]. Despite numerous studies reporting modulation of GJIC by chemicals and endogenous or exogenous ligands, the underlying intracellular mechanisms responsible for rapid inhibition of connexin- based cell-cell communication have not been fully elucidated
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