The Anti-proliferative Effects of Anandamide and Oleamide in Glioblastoma Cell Lines Recruit Mitochondrial and PPAR-γ Receptor Modulation

The endocannabinoid anandamide (AEA) and the related metabolite oleamide (ODA) have been demonstrated to possess anti-proliferative properties by recruiting apoptotic mechanisms in glioblastoma cells; however, the role of receptors other than the canonical cannabinoid receptors in their pattern of anti-proliferative mechanisms has been poorly investigated. Here, we evaluated the role of mitochondrial function and PPAR-γ membrane receptors in the anti-proliferative mechanisms induced by AEA and ODA in the glioblastoma cell lines C6 and RG2. Cell viability and lipid peroxidation assessments in both cell lines showed antiproliferative and pro-oxidant effects of the tested cannabinoids, respectively, compared to primary astrocyte cultures used as a non-tumor negative control. AEA and ODA also reduced mitochondrial membrane potential in C6, but not in RG2 cells, while impairing mitochondrial Complex I activity in C6. The PPAR-γ receptor antagonist GW9662 showed differential effects on the AEA- and ODA-induced loss of cell viability in both cell lines, as well as in mitochondrial membrane potential. The ontogenetic origin and metabolic differences between RG2 and C6 cell lines may establish differential responses evoked by endogenous cannabinoids and PPAR-γ receptor modulation. Combined, our results demonstrate that AEA and ODA modulate mitochondrial function in glioblastoma cells by inhibiting the activity of mitochondrial Complex 1, which in turn increases markers of oxidative damage and interferes with glioblastoma proliferation.