arachidonylcyclopropylamide and Adenocarcinoma

The pancreatic adenocarcinoma cell line Panc1 was treated with cannabinoid receptor ligands (arachidonylcyclopropylamide or GW405833) in order to elucidate the molecular mechanism of their anticancer effect. A proteomic approach was used to analyze the protein and phosphoprotein profiles. Western blot and functional data mining were also employed in order to validate results, classify proteins, and explore their potential relationships. We demonstrated that the two cannabinoids act through a widely common mechanism involving up- and down-regulation of proteins related to energetic metabolism and cell growth regulation. Overall, the results reported might contribute to the development of a therapy based on cannabinoids for pancreatic adenocarcinoma.

Topics: Adenocarcinoma; Arachidonic Acids; Cell Line, Tumor; Cell Proliferation; Humans; Indoles; Morpholines; Pancreas; Pancreatic Neoplasms; Phosphoproteins; Protein Interaction Maps; Proteome; Proteomics; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2

The anti-tumoral effects of cannabinoids have been described in different tumor systems, including pancreatic adenocarcinoma, but their mechanism of action remains unclear. We used cannabinoids specific for the CB1 (ACPA) and CB2 (GW) receptors and metabolomic analyses to unravel the potential pathways mediating cannabinoid-dependent inhibition of pancreatic cancer cell growth. Panc1 cells treated with cannabinoids show elevated AMPK activation induced by a ROS-dependent increase of AMP/ATP ratio. ROS promote nuclear translocation of GAPDH, which is further amplified by AMPK, thereby attenuating glycolysis. Furthermore, ROS determine the accumulation of NADH, suggestive of a blockage in the respiratory chain, which in turn inhibits the Krebs cycle. Concomitantly, inhibition of Akt/c-Myc pathway leads to decreased activity of both the pyruvate kinase isoform M2 (PKM2), further downregulating glycolysis, and glutamine uptake. Altogether, these alterations of pancreatic cancer cell metabolism mediated by cannabinoids result in a strong induction of autophagy and in the inhibition of cell growth.

Topics: Acetylcysteine; Adenocarcinoma; Adenosine Monophosphate; Adenosine Triphosphate; Adenylate Kinase; Antineoplastic Agents; Arachidonic Acids; Autophagy; Cannabinoids; Cell Line, Tumor; Cell Nucleus; Citric Acid Cycle; Drug Screening Assays, Antitumor; Energy Metabolism; Enzyme Activation; Glutamine; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); Glycolysis; Humans; Indoles; Morpholines; Pancreatic Neoplasms; Reactive Oxygen Species; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2