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Cannabinoids inhibit gap junctional intercellular communication and activate ERK in a rat liver epithelial cell line
Author(s) -
Upham Brad L.,
Rummel Alisa M.,
Carbone Joseph M.,
Trosko James E.,
Ouyang Yanli,
Crawford Robert B.,
Kaminski Norbert E.
Publication year - 2003
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.10899
Subject(s) - mapk/erk pathway , cannabinoid receptor , cannabinoid , intracellular , microbiology and biotechnology , biology , signal transduction , cell culture , epigenetics , cell growth , tumor promotion , receptor , cancer research , pharmacology , antagonist , carcinogenesis , biochemistry , genetics , cancer , gene
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 Δ 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 Δ 9 ‐THC and CBN reversibly inhibited GJIC at noncytotoxic doses (15 μM) 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. © 2002 Wiley‐Liss, Inc.