Hypoxia-induced inhibition of the endocannabinoid system in glioblastoma cells

Abstract

The endocannabinoid system plays an important role in the regulation of physiological and pathological conditions, including inflammation and cancer. Hypoxia is a fundamental phenomenon for the establishment and maintenance of the microenvironments in various physiological and pathological conditions. However, the influence of hypoxia on the endocannabinoid system is not fully understood. In the present study, we investigated the effects of hypoxia on the endocannabinoid system in malignant brain tumors. We subjected U-87 MG cells, derived from malignant glioblastoma, to hypoxia (1.5% O2) for 3 days, and evaluated their viability and expression of endocannabinoid-related genes. Hypoxia decreased the expression of cannabinoid receptor 1 and the astrocyte marker glial fibrillary acidic protein, and increased the expression of vascular endothelial growth factor and cyclooxygenase-2, the enzyme responsible for the metabolism of endocannabinoids, in U-87 MG cells. Although cannabinoid receptor (CB) engagement induces cell death in U-87 MG cells in normoxic conditions, CB agonist-induced death was attenuated in hypoxic conditions. These results suggest that hypoxia modifies the endocannabinoid system in glioblastoma cells. Hypoxia-induced inhibition of the endocannabinoid system may aid the development of glioblastoma.

Corticosterone inhibits the expression of cannabinoid receptor‑1 and cannabinoid receptor agonist‑induced decrease in cell viability in glioblastoma cells

“…These results suggest that CB1 might not be committed to cell viability directly in U-87 cells. However, as shown in our previous study that hypoxia decreased the expression of CB1 in U-87 MG cells, the cannabinoid receptor agonist WIN 55,212-2 decreased glioblastoma cell viability, with the extent depending on the expression level of the CB1 receptor (5). In the present study, we showed that corticosterone downregulated the expression of CB1 and suppressed WIN 55,212-2-induced decrease in U-87 MG cell viability.…”

“…Interestingly, emotional and physical stressors release corticosteroids and, in turn, impair the endocannabinoid system (8). We previously showed that hypoxia aggravates cancer by inhibiting the endocannabinoid system in malignant glioblastoma cells (5). Thus, dysfunction of the endocannabinoid system by stress-released corticosteroids may lead to the development and progression of malignancies.…”

“…Recently, cannabinoid receptor agonists were shown to mimic the effects of endogenous cannabinoids and cause cell death in glioblastoma (5,11,12). The observed corticosterone-induced downregulation of cannabinoid receptor expression; thus, we investigated the effects of 48 h treatment with CORT on cannabinoid receptor agonist-induced decrease in glioblastoma cell viability.…”

“…We found that corticosterone inhibits the expression of the genes encoding CB1 and attenuates cannabinoid receptor Cell viability assay. Cell viability was analyzed using the Cell Counting Kit-8 (Wako Pure Chemical Industries) as previously described (5,9). U-87 MG cells were seeded into 96-well plates at a density of 1x10 2 cells/well.…”

Modulations of Neuroendocrine Stress Responses During Confinement in Antarctica and the Role of Hypobaric Hypoxia

“…In the tumor microenvironment, hypoxia is known to upregulate the expression of cyclooxygenase-2 (COX-2) via hypoxia-inducible factor-1 (HIF-1) signaling ( Greenhough et al, 2009 ). COX-2 is one of the enzymes responsible for metabolism of ECs ( Sugimoto et al, 2017 ) with the main substrates being AEA and 2-AG ( Chiurchiu et al, 2015 ). Therefore, missing upregulation of ECs at Concordia (high altitude) might be due to hypoxia-induced upregulation of COX-2 (and possibly other enzymes) which in turn oxidizes ECs into compounds (e.g., prostaglandin-ethanolamides, hydroxy-AEAs) ( Chiurchiu et al, 2015 ) that were beyond the scope of our investigations.…”