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Cannabinoids inhibit gap junctional intercellular communication and activate ERK in a rat liver epithelial cell line
Brad L Upham1, Alisa M Rummel, Joseph M Carbone
1Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI 48824-1302,USA. upham@msu.edu
Abstract:
Many tumor promoters suppress the immune system; however, the direct effect of immunosuppressants on the tumorigenic pathways of nonimmune cells in solid tissue has not been well documented. Cannabinoids were chosen to explore this question further. Cannabinoids are immune modulators that affect specific intracellular signaling pathways in leukocytes. Since these compounds are nongenotoxic, any tumorigenic effect that might be associated with these compounds would need to occur through an epigenetic mechanism. Therefore, we determined the effect of Delta(9)-THC and CBN, 2 plant-derived cannabinoids, on 2 key epigenetic markers of tumor promotion: inhibition of GJIC, which is essential in removing a cell from growth suppression, and activation of the ERK-MAPK pathway, which is crucial in activating the appropriate genes for mitogenesis. Both Delta(9)-THC and CBN reversibly inhibited GJIC at noncytotoxic doses (15 microM) in a normal diploid WB rat liver epithelial oval cell line within 20 min and activated ERK1 and ERK2 within 5 min. Inhibition of MEK with PD98059 prevented the inhibition of GJIC by either cannabinoid, suggesting that inhibition of GJIC was MEK-dependent. Based on RT-PCR analysis and employment of an antagonist of CB1 and CB2, the effects on GJIC and MAPK were independent of both cannabinoid receptors. Cannabinoids affected crucial epigenetic pathways associated with cell proliferation in a rodent liver epithelial cell model system.
Insights
Cannabinoids like Delta(9)-THC and CBN can epigenetically promote tumors by inhibiting gap junction intercellular communication (GJIC) and activating the ERK-MAPK pathway in non-immune cells.
Area of Science:
- Epigenetics and Cancer Biology
- Molecular Pharmacology of Cannabinoids
Background:
- Tumor promoters often suppress the immune system, but their direct impact on non-immune cell tumorigenesis via immunosuppression is understudied.
- Cannabinoids, known immune modulators, were investigated for potential epigenetic effects on tumor promotion pathways due to their non-genotoxic nature.
Purpose of the Study:
- To investigate the direct effects of plant-derived cannabinoids, Delta(9)-THC and CBN, on key epigenetic markers of tumor promotion in non-immune cells.
- To determine if cannabinoids influence gap junction intercellular communication (GJIC) and the ERK-MAPK pathway, critical for cell proliferation and growth suppression.
Main Methods:
- Assessed the impact of Delta(9)-THC and CBN on GJIC and ERK-MAPK activation in a rat liver epithelial cell line.
- Utilized MEK inhibition (PD98059) to explore the dependency of these effects on the MAPK pathway.
- Investigated the role of cannabinoid receptors (CB1 and CB2) using RT-PCR and receptor antagonists.
Main Results:
- Both Delta(9)-THC and CBN reversibly inhibited GJIC and activated ERK1/ERK2 at non-cytotoxic concentrations.
- MEK inhibition blocked cannabinoid-induced GJIC inhibition, indicating a MEK-dependent mechanism.
- The observed effects on GJIC and MAPK were independent of CB1 and CB2 cannabinoid receptors.
Conclusions:
- Plant-derived cannabinoids can modulate crucial epigenetic pathways involved in cell proliferation.
- These cannabinoids may promote tumorigenesis through mechanisms independent of cannabinoid receptors, affecting GJIC and MAPK signaling in liver epithelial cells.