Cannabinoids inhibit gap junctional intercellular communication and activate ERK in a rat liver epithelial cell line.
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.
Upham
Brad L
BL
Department of Pediatrics and Human Development, Michigan State University, East Lansing, MI 48824-1302,USA. upham@msu.edu
Rummel
Alisa M
AM
Carbone
Joseph M
JM
Trosko
James E
JE
Ouyang
Yanli
Y
Crawford
Robert B
RB
Kaminski
Norbert E
NE
D000818:Animals; D001892:Camphanes / Q000494:pharmacology; D002187:Cannabinol / Q000494:pharmacology*; D002450:Cell Communication / Q000187:drug effects*; D002460:Cell Line / Q000187:drug effects / Q000201:enzymology; D000242:Cyclic AMP / Q000378:metabolism; D013759:Dronabinol / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D005419:Flavonoids / Q000494:pharmacology; D017629:Gap Junctions / Q000187:drug effects*; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000187:drug effects / Q000502:physiology; D000077285:Rimonabant
D001892:Camphanes; C469526:Cnr2 protein, rat; D004791:Enzyme Inhibitors; D005419:Flavonoids; D010880:Piperidines; D011720:Pyrazoles; D012333:RNA, Messenger; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C110630:SR 144528; D013759:Dronabinol; D002187:Cannabinol; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D000077285:Rimonabant; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one