Abstract
The heterogeneity of tumor cell mass and the plasticity of cancer cell phenotypes in solid tumors allow for the insurgence of resistant and metastatic cells, responsible for cancer patients’ clinical management’s main challenges. Among several factors that are responsible for increased cancer aggression, metabolic reprogramming is recently emerging as an ultimate cancer hallmark, as it is central for cancer cell survival and self-renewal, metastasis and chemoresistance. The P2X7 receptor, whose expression is upregulated in many solid and hematological malignancies, is also emerging as a good candidate in cancer metabolic reprogramming and the regulation of stem cell proliferation and differentiation. Metabostemness refers to the metabolic reprogramming of cancer cells toward less differentiated (CSCs) cellular states, and we believe that there is a strong correlation between metabostemness and P2X7 receptor functions in oncogenic processes. Here, we summarize important aspects of P2X7 receptor functions in normal and tumor tissues as well as essential aspects of its structure, regulation, pharmacology and its clinical use. Finally, we review current knowledge implicating P2X7 receptor functions in cancer-related molecular pathways, in metabolic reprogramming and in metabostemness.
Highlights
In the context of metabolic reprogramming, cancer stem cells (CSC) have a mitochondria-centric energy metabolism, giving them the ability to consume limited available nutrients, such as fatty acids to generate ATP, NADPH, tricarboxylic acid (TCA) cycle intermediates, nucleotide bases, electron acceptors and others, favoring cancer cell survival and proliferation signaling [49] and epigenetic regulation, and by genetic-independent mechanisms tightly related to metabolic reprogramming [22,59]
The P2X7 receptor has been related to Fatty acid (FA) metabolism in a way that P2X7KO mice presented reduction at mRNA and protein expression level of key enzymes, such as fatty acid synthase (FASN)
Other key proteins of signaling pathways, which were in their expression levels upregulated in acute myeloid leukemia (AML) by P2X7 receptors, include cAMP response element-binding protein (CREB) [79], Pre-B cell leukemia transcription factor 3 (Pbx3) [80] and c-myc [81]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The absence of the P2X7 receptor reduces mRNA and protein expression of fatty acid metabolism key enzymes, such as FASN and acetyl-CoA carboxylase (ACC), and increases serum triglyceride and cholesterol levels, glucose intolerance and insulin resistance, which decreases stemness, proliferation, survival, invasiveness and therapeutic resistance [21] This evidences strongly correlate the involvement of the receptor in metabostemness and metabolic reprogramming of cancer cells. P2X7A has a C-terminal crucial for opening membrane large pores causing apoptosis, while P2X7B has a reduced C-terminal, being incapable of inducing cell death [11], while it is able to promote proliferation of stem and tumor cells [43,44] and participates in the cell differentiation process [44]. P2X7 isoforms on cancer metabolism may open avenues to more efficient therapy against chemoresistant and metastatic tumor
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