Purinergic receptors are a key bottleneck in tumor metabolic reprogramming: The prime suspect in cancer therapeutic resistance

Abstract

ATP and other nucleoside phosphates have specific receptors named purinergic receptors. Purinergic receptors and ectonucleotidases regulate various signaling pathways that play a role in physiological and pathological processes. Extracellular ATP in the tumor microenvironment (TME) has a higher level than in normal tissues and plays a role in cancer cell growth, survival, angiogenesis, metastasis, and drug resistance. In this review, we investigated the role of purinergic receptors in the development of resistance to therapy through changes in tumor cell metabolism. When a cell transforms to neoplasia, its metabolic processes change. The metabolic reprogramming modified metabolic feature of the TME, that can cause impeding immune surveillance and promote cancer growth. The purinergic receptors contribute to therapy resistance by modifying cancer cells’ glucose, lipid, and amino acid metabolism. Limiting the energy supply of cancer cells is one approach to overcoming resistance. Glycolysis inhibitors which reduce intracellular ATP levels may make cancer cells more susceptible to anti-cancer therapies. The loss of the P2X7R through glucose intolerance and decreased fatty acid metabolism reduces therapeutic resistance. Potential metabolic blockers that can be employed in combination with other therapies will aid in the discovery of new anti-cancer immunotherapy to overcome therapy resistance. Therefore, therapeutic interventions that are considered to inhibit cancer cell metabolism and purinergic receptors simultaneously can potentially reduce resistance to treatment.

Diverse temporal and spatial mechanisms work, partially through Stanniocalcin-1, V-ATPase and senescence, to activate the extracellular ATP-mediated drug resistance in human cancer cells

“…In this model, eATP induces and regulates drug resistance spatially and temporally through multiple pathways and processes. First, eATP induces drug resistance extracellularly by binding to and activating purinergic receptors (PRs) located on the plasma membrane of cancer cells ( 29 – 31 , 44 , 45 ). The activated PRs (e.g.…”

Transcriptomic and metabolomic analysis of peri-tumoral hepatic tissue in hepatocellular carcinoma: unveiling the molecular landscape of immune checkpoint therapy resistance

“…However, not all sunshine and roses, the therapeutic landscape of HCC is punctuated by instances of resistance to immune checkpoint therapies. This phenomenon of immunotherapy resistance is both intricate and multifaceted, often serving as a significant bottleneck to realizing the full therapeutic potential of these novel interventions ( Zhang et al, 2021 ; Aria et al, 2022 ). It is within this challenging context that our study attempts to shed light on the molecular actors that might play pivotal roles in determining treatment outcomes.…”

The potential value of the Purinergic pathway in the prognostic assessment and clinical application of kidney renal clear cell carcinoma

“…However, abnormal changes in the Purinergic pathway may lead to the development of various diseases, including many cancers [9]. Recent studies have shown that tumor cells can use the Purinergic pathway to promote their proliferation, invasion, angiogenesis, and immune escape by increasing the production and release of purine nucleotide derivatives and altering the expression and sensitivity of Purinergic receptors [10]. At the same time, immune cells in the tumor microenvironment can also interact with tumor cells through the Purinergic pathway, thereby affecting tumor cell growth and metastasis [11].…”