Negative regulation of cannabinoid receptor 2‑induced tumorigenic effect by sphingosine‑1‑phosphate receptor 5 activation.

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G protein‑coupled receptors (GPCR), also known as seven‑transmembrane proteins, serve a role in transmitting extracellular information into the cellular environment. Type 2 cannabinoid receptors (CB2) and type 5 sphingosine‑1‑phosphate receptor (S1P5) are GPCRs that are activated by biolipids and involved in tumor progression in various cancer types. At present, effects of crosstalk between CB2 and S1P5 receptors on tumor cell proliferation and migration in gliomas are not fully understood. The present study screened S1Ps for potential interactions with CB2 using bioluminescence resonance energy transfer analysis. S1P5 interacted strongly and specifically with CB2. 293T cells were transfected with CB2 tagged with Venus and S1P5 tagged with mCherry to investigate the cellular localization of both receptors. After 24 h, Confocal microscopy analysis revealed that, in the absence of agonists, both receptors were predominantly localized at the plasma membrane. Notably, both receptors were co‑internalized from the membrane to the cytoplasm upon individual and combined activation. The effects of co‑activation of both receptors on tumor progression were investigated using U‑87 MG, the human glioblastoma cell line. Activation of CB2 induced an increase in cell migration and proliferation, which were downregulated following the co‑activation of S1P5. Furthermore, activation of S1P5 significantly attenuated the upregulation of tumor progression‑related genes, including zinc finger protein 91, activating transcription factor 3, Ki67, basic transcription factor 3, and p21, induced by CB2 activation. This suggests that S1P5 exerts a negative regulatory effect on CB2‑mediated tumor progression. The present findings provide evidence of the crosstalk between CB2 and S1P5.