The
endocannabinoids anandamide (AEA) and
2-arachidonylglycerol (2-AG) have opposing effects on
cholangiocarcinoma growth. Implicated in
cancer, Notch signaling requires the
gamma-secretase complex for activation. The aims of this study were to determine if the opposing effects of
endocannabinoids depend on the differential activation of the
Notch receptors and to demonstrate that the differential activation of these receptors are due to
presenilin 1 containing- and
presenilin 2 containing-
gamma-secretase complexes. Mz-ChA-1 cells were treated with AEA or 2-AG.
Notch receptor expression, activation, and nuclear translocation were determined. Specific roles for Notch 1 and 2 on
cannabinoid-induced effects were determined by transient transfection of Notch 1 or 2
shRNA vectors before stimulation with AEA or 2-AG. Expression of
presenilin 1 and 2 was determined after AEA or 2-AG treatment, and the involvement of
presenilin 1 and 2 in the
cannabinoid-induced effects was demonstrated in cell lines with low
presenilin 1 or 2 expression. Antiproliferative effects of AEA required increased Notch 1
mRNA, activation, and nuclear translocation, whereas the growth-promoting effects induced by 2-AG required increased Notch 2
mRNA expression, activation, and nuclear translocation. AEA increased
presenilin 1 expression and recruitment into the
gamma-secretase complex, whereas 2-AG increased expression and recruitment of
presenilin 2. The development of novel therapeutic strategies aimed at modulating the
endocannabinoid system or mimicking the mode of action of AEA on Notch signaling pathways would prove beneficial for
cholangiocarcinoma management.