Cannabinoids inhibit gap junctional intercellular communication and activate ERK in a rat liver epithelial cell line

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 ⌬ 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 ⌬ 9 -THC and CBN reversibly inhibited GJIC at noncytotoxic doses (15 M) 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.

Altered Tumor Biology and Tumorigenesis in Irradiated and Chemical Carcinogen-Treated Single and Combined Connexin32/p27Kip1-Deficient Mice

“…Here we showed preferential origination/selection of liver and lung tumors exhibiting increased MAPK activation from Cx32-KO mice. Interestingly, MAPK has been shown to directly modulate connexin/GJIC life cycle and activity via Cx43 phosphorylation both in vitro and in vivo (38)(39)(40)(41).…”

Deficiency in the gap junction protein Connexin32 alters p27Kip1 tumor suppression and MAPK activation in a tissue-specific manner

“…Similar to lung, the number of MAPK-activated liver tumors diminished in the absence of p27 indicating some interaction between Cx32 and p27 in the origination/ progression of MAPK-active liver tumors. Interestingly, MAPK has previously been shown to directly modulate connexin/GJIC life cycle and activity both in vitro and in vivo (Warn-Cramer et al, 1996;Warn-Cramer et al, 1998;Defamie et al, 2003), particularly with an association between decreased GJIC and increased MAPK activation (Upham et al, 2003).…”

Cannabinoid activation of peroxisome proliferator-activated receptors: Potential for modulation of inflammatory disease

“…For example, statins enhance PPAR function in macrophages through activation of mitogen-activated protein kinase pathways (Yano et al 2007), which can also be activated by cannabinoid receptor stimulation (Rubino et al 2005;Upham et al 2003;Demuth and Molleman 2006).…”