P2X7 receptor in normal and cancer cells in the perspective of nucleotide signaling

Abstract

Nucleotides are the most common compounds produced constantly by living organisms. They are involved in most cellular processes like the synthesis of other nucleotides and nucleic acids, generation of energy needed for the maintenance of cells, and molecular signaling. In the 70s sir. Geoffrey Burstock discovered a new class of transmembrane proteins – nucleotide receptors responding to nucleotides and their derivatives. For historical reasons, we distinguish two main classes of nucleotide receptors: P1 – which are G protein-coupled adenosine receptors, and P2 – nucleotide receptors that respond to ATP and its derivatives. Additionally, the P2 receptors family can be divided into two subgroups: P2Y – G protein-coupled receptors and P2X cation channel receptors. This paper focuses mainly on the most researched receptor in the nucleotide receptors family – the P2X7 receptor – presenting it in the background of the nucleotide signaling landscape. Almost thirty years of extensive studies on the receptor contributed to understanding protein structure, splicing variants, and mechanism of action in somatic cells. Despite such a wide spectrum of research, the role of the receptor in cancer progression is still undetermined. In many reports, we can find information about the anti-tumorigenic role of this receptor caused by activation of the cell death mechanism after membrane pore formation. These results, however, contradict other studies in which the same receptor is known to promote cancer development through stimulation of proliferation and activation of pro-survival pathways. Ultimately, all this gathered knowledge points to two faces of the receptor in tumor progression. Therefore, we do provide a comprehensive overview of the topic. Finally, we also try to systemize previous and recent literature about the role of this receptor in somatic and cancer cells and provide access to it in the form of a convenient table.

Purinergic P2X7 Receptor as a Potential Targeted Therapy for COVID-19-associated Lung Cancer Progression

“…SARS-CoV-2 may hyperactivate P2X7R by increasing extracellular ATP levels. It can activate multiple signaling pathways, including NLRP3 (inflammasome), JNK, Rho kinase, HMGB1-RAGE, PI3K/AKT, HIF-1α, and ERK [1,20,[22][23][24]35]. In this regard, IL-1β and IL-18 pro-inflammatory cytokines are released after NLRP3 inflammasome activation.…”

“…As SARS-CoV-2 primarily affects lung tissue and leads to severe acute respiratory syndrome, individuals with respiratory disorders, such as lung cancer, may be more susceptible to COVID-19 and should be given extra attention [33,34]. In this line, previous studies indicated that P2X7R could cause carcinogenesis, progression, survival, and metastasis of lung cancer cells through its up-regulation and activation of numerous intracellular signaling pathways such as JNK, Rho, HMGB1, and Epithelial-Mesenchymal Transition (EMT) pathways in bronchoalveolar cells [35,36]. In normal cells, the P2X7 receptor has moderate activity because of its smooth affinity for low concentrations of ATP.…”

“…Increased aerobic glycolysis in cancerous cells will result in hyper-activated mitochondria leading to Ca 2+ release from the endoplasmic reticulum and subsequently, high levels of ATP. A high concentration of ATP can promote lung cancer cells' progression and survival through the activation of P2X7 receptor [35]. Also, the P2X7R activation itself can increase the cytosolic Ca 2+ and ratio of Bcl-2/Bax ratio to promote cancer cell survival [36].…”