To inhibit or to boost the ATP/P2RX7 pathway to fight cancer—that is the question

Hreich, Serena Janho dit; Benzaquen, Jonathan; Hofman, Paul; Vouret‐Craviari, Valérie

doi:10.1007/s11302-021-09811-9

Cited by 14 publications

(10 citation statements)

References 143 publications

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“…One of the ICD-relevant pathways involves the autophagy-dependent lysosomal secretion of adenosine triphosphate (ATP), the ligand of P2RX7. 131–136 The relevance of the autophagic pathway in the context of the HNSCC has already been described: rs1864183 in ATG10 , rs3759601 in ATG2B and rs2241880 in ATG16L1 were found to be associated with an higher susceptibility to develop HNSCC (laryngeal, pharyngeal, and oral carcinoma, respectively) in a Spanish population. 137 Given these premises, we decided to investigate the role of rs2241880 in our cohort of patients, knowing that rs2241880 affects ATG16L1 , which encodes a central adaptor required for the formation of the autophagosome.…”

Section: Resultsmentioning

confidence: 87%

A loss-of-function polymorphism in ATG16L1 compromises therapeutic outcome in head and neck carcinoma patients

et al. 2022

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The anticancer immune response is shaped by immunogenic cell stress and death pathways. Thus, cancer cells can release danger-associated molecular patterns that act on pattern recognition receptors expressed by dendritic cells and their precursors to elicit an antitumor immune response. Here, we investigated the impact of single nucleotide polymorphisms (SNPs) in genes affecting this cancer-immunity dialogue in the context of head and neck squamous cell carcinoma (HNSCC). We observed that homozygosity for a loss-of-function SNP (rs2241880, leading to the substitution of a threonine residue in position 300 by an alanine) affecting autophagy related 16 like 1 (ATG16L1) is coupled to poor progression-free survival in platinum-treated HNSCC patients. This result was obtained on a cohort of patients enrolled at the Gustave Roussy Cancer Campus and was validated on an independent cohort of The Cancer Genome Atlas (TCGA). Homozygosity in rs2241880 is well known to predispose to Crohn’s disease, and epidemiological associations between Crohn’s disease and HNSCC have been reported at the levels of cancer incidence and prognosis. We speculate that rs2241880 might be partially responsible for this association.

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Section: Resultsmentioning

confidence: 87%

A loss-of-function polymorphism in ATG16L1 compromises therapeutic outcome in head and neck carcinoma patients

et al. 2022

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“…The composition of TME is complex, containing non-cancerous cells, extracellular matrix and specific physicochemical conditions. Extracellular ATP (eATP) within TME is well investigated as an important signaling molecule, which can regulate a series of biological processes by binding to P2RX7 [ 75 ]. It is notable that eATP concentration measured in tumors (50–500 μmol/L) are dramatically higher than those in healthy tissues (10–100 μmol/L) [ 76 – 78 ].…”

Section: Discussionmentioning

confidence: 99%

P2RX7 promotes osteosarcoma progression and glucose metabolism by enhancing c-Myc stabilization

et al. 2023

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Background Osteosarcoma is the most common malignant tumor in bone and its prognosis has reached a plateau in the past few decades. Recently, metabolic reprogramming has attracted increasing attention in the field of cancer research. In our previous study, P2RX7 has been identified as an oncogene in osteosarcoma. However, whether and how P2RX7 promotes osteosarcoma growth and metastasis through metabolic reprogramming remains unexplored. Methods We used CRISPR/Cas9 genome editing technology to establish P2RX7 knockout cell lines. Transcriptomics and metabolomics were performed to explore metabolic reprogramming in osteosarcoma. RT-PCR, western blot and immunofluorescence analyses were used to determine gene expression related to glucose metabolism. Cell cycle and apoptosis were examined by flowcytometry. The capacity of glycolysis and oxidative phosphorylation were assessed by seahorse experiments. PET/CT was carried out to assess glucose uptake in vivo. Results We demonstrated that P2RX7 significantly promotes glucose metabolism in osteosarcoma via upregulating the expression of genes related to glucose metabolism. Inhibition of glucose metabolism largely abolishes the ability of P2RX7 to promote osteosarcoma progression. Mechanistically, P2RX7 enhances c-Myc stabilization by facilitating nuclear retention and reducing ubiquitination-dependent degradation. Furthermore, P2RX7 promotes osteosarcoma growth and metastasis through metabolic reprogramming in a predominantly c-Myc-dependent manner. Conclusions P2RX7 plays a key role in metabolic reprogramming and osteosarcoma progression via increasing c-Myc stability. These findings provide new evidence that P2RX7 might be a potential diagnostic and/or therapeutic target for osteosarcoma. Novel therapeutic strategies targeting metabolic reprogramming appear to hold promise for a breakthrough in the treatment of osteosarcoma.

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“…Continual proliferation characterizes tumor cells and growth factors stimulate cell proliferation through receptors with intracellular tyrosine kinase domains ( 238 ). ATP is not a member of the growth factor family and P2RX7 has no tyrosine kinase domains; however, low concentration of ATP activates P2RX7, cell proliferation ( 111 , 200 , 239 – 241 ), and kinase activity ( 242 ). P2RX7 activated cellular sarcoma tyrosine kinase (c-Src), PI3-K/Akt, MAPKs (ERK1/2, p38, and JNK), and protein kinase C (PKC) ( 243 ).…”

Section: Purinergic Signaling In Cell Proliferation and Deathmentioning

confidence: 99%

Purinergic signaling: Diverse effects and therapeutic potential in cancer

Kaur

Dora

2023

Front. Oncol.

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Regardless of improved biological insights and therapeutic advances, cancer is consuming multiple lives worldwide. Cancer is a complex disease with diverse cellular, metabolic, and physiological parameters as its hallmarks. This instigates a need to uncover the latest therapeutic targets to advance the treatment of cancer patients. Purines are building blocks of nucleic acids but also function as metabolic intermediates and messengers, as part of a signaling pathway known as purinergic signaling. Purinergic signaling comprises primarily adenosine triphosphate (ATP) and adenosine (ADO), their analogous membrane receptors, and a set of ectonucleotidases, and has both short- and long-term (trophic) effects. Cells release ATP and ADO to modulate cellular function in an autocrine or paracrine manner by activating membrane-localized purinergic receptors (purinoceptors, P1 and P2). P1 receptors are selective for ADO and have four recognized subtypes—A1, A2A, A2B, and A3. Purines and pyrimidines activate P2 receptors, and the P2X subtype is ligand-gated ion channel receptors. P2X has seven subtypes (P2X1–7) and forms homo- and heterotrimers. The P2Y subtype is a G protein-coupled receptor with eight subtypes (P2Y1/2/4/6/11/12/13/14). ATP, its derivatives, and purinoceptors are widely distributed in all cell types for cellular communication, and any imbalance compromises the homeostasis of the cell. Neurotransmission, neuromodulation, and secretion employ fast purinergic signaling, while trophic purinergic signaling regulates cell metabolism, proliferation, differentiation, survival, migration, invasion, and immune response during tumor progression. Thus, purinergic signaling is a prospective therapeutic target in cancer and therapy resistance.

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To inhibit or to boost the ATP/P2RX7 pathway to fight cancer—that is the question

Cited by 14 publications

References 143 publications

A loss-of-function polymorphism in ATG16L1 compromises therapeutic outcome in head and neck carcinoma patients

A loss-of-function polymorphism in ATG16L1 compromises therapeutic outcome in head and neck carcinoma patients

P2RX7 promotes osteosarcoma progression and glucose metabolism by enhancing c-Myc stabilization

Purinergic signaling: Diverse effects and therapeutic potential in cancer

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