Figure 1.

The effect of purinergic receptors on tumorigenesis and tumor cell metabolism. After binding to ATP, the purinergic receptor, P2X7R, removes K⁺ from the cell as Ca²⁺ and Na⁺ enter the cell. Also, extracellular ATP, due to the enzymatic function of CD39 and CD73, is converted to AMP and ADO. By binding to P1 receptors, ADO has tumor-promoting effects by inhibiting the immune response. Stimulation of the P1 receptor also causes activation of Akt and HIF-1a. An increase in intracellular Ca²⁺ activates PKC and PI3K, and PI3K by converting PIP2 to PIP3 activates Akt. As the main regulator, Akt activates HIF-1a, mTOR/VEGF, and NF-kb pathways and inactivates GSK-3, eventually leading to apoptosis inhibition, EMT, invasion, survival, and proliferation. Akt stimulates the glycolysis pathway. Glycolysis and OXPHOS or cell damage can produce ATP, leaving the cell through the PANX receptor. After binding to ATP, another purinergic receptor, P2YR, can increase ICAM-1, VCAM-1, and MMP, leading to adhesion and invasion of tumor cells. ADO, adenosine; AMP, adenosine monophosphate; ATP, adenosine triphosphate; CD39, cluster of differentiation 39; CD73, cluster of differentiation 73; DC, dendritic cell; EMT, epithelial-mesenchymal transition; GSK-3, glycogen synthase kinase-3; HIF-1a, hypoxia-inducible factor 1-alpha; ICAM-1, intercellular Adhesion Molecule 1; MMP, matrix metallopeptidase; mTOR, mammalian target of rapamycin; NF-kb, nuclear factor kappa B; NK cell, natural killer cell; OXPHOS, oxidative phosphorylation; PANX, pannexin; PI3K, phosphoinositide 3-kinases; PIP2, phosphatidylinositol-4, 5-bisphosphate; PIP3, phosphatidylinositol-3, 4, 5-triphosphate; PKC, protein kinase C; TAM, tumor-associated macrophage; Th2, T helper type 2; Treg, regulatory T cell; VCAM-1, vascular cell adhesion molecule 1; VEGF, vascular endothelial growth factor.