title: Cannabinoids inhibit energetic metabolism and induce AMPK-dependent autophagy in pancreatic cancer cells.
abstract: 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.
authors.affiliation: Department of Life and Reproduction Sciences, Biochemistry Section, University of Verona, Verona, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Dando
authors.forename: M
authors.initials: M
authors.lastname: Donadelli
authors.forename: C
authors.initials: C
authors.lastname: Costanzo
authors.forename: E
authors.initials: E
authors.lastname: Dalla Pozza
authors.forename: A
authors.initials: A
authors.lastname: D'Alessandro
authors.forename: L
authors.initials: L
authors.lastname: Zolla
authors.forename: M
authors.initials: M
authors.lastname: Palmieri
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000230:Adenocarcinoma; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000494:pharmacology*; D001343:Autophagy; D002186:Cannabinoids / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology; D002952:Citric Acid Cycle / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004734:Energy Metabolism; D004789:Enzyme Activation; D005973:Glutamine / Q000378:metabolism; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology*; D010190:Pancreatic Neoplasms; D017382:Reactive Oxygen Species / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists
chemical_list: C463040:1-(2,3-dichlorobenzoyl)-5-methoxy-2-methyl-(2-(mopholin-4-yl)ethyl)-1H-indole; D000970:Antineoplastic Agents; D001095:Arachidonic Acids; D002186:Cannabinoids; D007211:Indoles; D009025:Morpholines; D017382:Reactive Oxygen Species; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C119324:arachidonylcyclopropylamide; D005973:Glutamine; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D000263:Adenylate Kinase; D000111:Acetylcysteine