Cannabinoids inhibit energetic metabolism and induce AMPK-dependent autophagy in pancreatic cancer cells

The anti-tumoral effects of cannabinoids have been described in different tumor systems, but their mechanism of action remains unclear. The aim of this thesis was to unravel key pathways mediating cannabinoid dependent inhibition of pancreatic cancer cell growth through the analysis of energetic metabolism. Panc1 cells treated with two synthetic cannabinoids, GW and ACPA, showed elevated AMPK activation induced by a ROS-dependent increase of AMP:ATP ratio. ROS promoted nuclear translocation of GAPDH, which was further amplified by AMPK, thereby attenuating glycolysis. Furthermore, ROS determined the accumulation of NADH, suggestive of a blockage in the respiratory chain, which in turn inhibited the Krebs cycle. Concomitantly, inhibition of Akt/c-Myc pathway led to a decreased activity of pyruvate kinase isoform M2 (PKM2), further down-regulating glycolysis, and glutamine uptake. Altogether, these alterations of cancer cell metabolism mediated by cannabinoids resulted in a strong induction of autophagy and inhibition of cell growth.