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

Abstract

Background Osteosarcoma is the most common malignant tumor in bone and the prognosis has reached a plateau in the past few decades. Recently, metabolic reprogramming has attracted increasing attention in the research on cancer progression. In our previous study, P2RX7 has been determined as on 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 verify metabolic reprogramming in osteosarcoma. RT-PCR, western blot and immunofluorescence analyses were used to determine glucose metabolism related gene expressions. Cell cycle and apoptosis were examined by flowcytometry. The capacity of glycolysis and oxidative phosphorylation were evaluated 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 various glucose metabolism related gene expressions. 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 c-Myc stability. These findings provide new evidence that P2RX7 might be a novel diagnostic and/or therapeutic target in osteosarcoma. Novel therapeutic strategies targeting metabolic reprogramming appears to be promising as an alternative in osteosarcoma treatment.