Opposing actions of endocannabinoids on cholangiocarcinoma growth is via the differential activation of Notch signaling

Exp Cell Res. 2010 May 15;316(9):1465-78. doi: 10.1016/j.yexcr.2010.03.017. Epub 2010 Mar 25.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases
  • Animals
  • Arachidonic Acids / pharmacology
  • Bile Duct Neoplasms / drug therapy
  • Bile Duct Neoplasms / metabolism
  • Bile Duct Neoplasms / pathology*
  • Bile Ducts, Intrahepatic / drug effects
  • Bile Ducts, Intrahepatic / metabolism
  • Bile Ducts, Intrahepatic / pathology*
  • Blotting, Western
  • Cannabinoid Receptor Modulators / pharmacology*
  • Cell Proliferation / drug effects
  • Cholangiocarcinoma / drug therapy
  • Cholangiocarcinoma / metabolism
  • Cholangiocarcinoma / pathology*
  • Endocannabinoids*
  • Fluorescent Antibody Technique
  • Glycerides / pharmacology
  • Humans
  • Immunoenzyme Techniques
  • Immunoprecipitation
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Polyunsaturated Alkamides / pharmacology
  • Presenilin-1 / genetics
  • Presenilin-1 / metabolism
  • Presenilin-2 / genetics
  • Presenilin-2 / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptor, Notch1 / metabolism*
  • Receptor, Notch2 / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Arachidonic Acids
  • Cannabinoid Receptor Modulators
  • Endocannabinoids
  • Glycerides
  • Polyunsaturated Alkamides
  • Presenilin-1
  • Presenilin-2
  • RNA, Messenger
  • Receptor, Notch1
  • Receptor, Notch2
  • glyceryl 2-arachidonate
  • Amyloid Precursor Protein Secretases
  • anandamide