Abstract
Extracellular ATP in the tumor microenvironment exhibits either pro- or antitumor effect via interaction with P2Y receptors, but the intracellular signaling and functional roles of P2Y receptors in oral squamous cell carcinoma (OSCC) are unclear. We aimed to study the effect of ATP on OSCC cell lines and the potential mechanisms involved. Through GEPIA dataset analysis, high expression levels of mRNA encoding P2Y receptors, the ATP-induced G protein-coupled receptors, were associated with better overall patient survival in head and neck squamous cell carcinoma. qPCR analysis showed that the poorly differentiated OSCC SAS cell line, had higher P2RY1 expression level compared to the well-differentiated H103 and H376 cell lines. Western blotting and flow cytometry analyses revealed that ATP phosphorylated ERK and elevated intracellular calcium signaling in all tested cell lines. A significant S-phase cell cycle arrest was observed in SAS, and preincubation with the MEK inhibitor PD0325901 reversed the ATP-induced S-phase arrest. We further demonstrated that ATP induced a slight reduction in cell count and colony formation yet significant apoptosis in SAS. Overall, we postulate that the ATP-induced S-phase arrest effect in SAS cells may be regulated through P2Y receptor-mediated ERK signaling, thus suggesting a potential antitumor effect of ATP via interaction with its distinct profile of P2Y receptors.
Highlights
Oral squamous cell carcinoma (OSCC) is one of the common malignant types of head and neck cancers and accounts for 3% of malignant tumors worldwide [1]
head and neck squamous cell carcinoma (HNSCC) samples expressed slightly higher P2RY11 compared to the normal tissues, and its high expression was associated with longer survival
Our qPCR findings showed that the earlier stage cancer cell lines, H103 and SAS, had high expression of genes encoding P2Y1 and P2Y2 receptors compared to the later stage OSCC cell line, H376
Summary
Oral squamous cell carcinoma (OSCC) is one of the common malignant types of head and neck cancers and accounts for 3% of malignant tumors worldwide [1]. Despite advancement in therapeutic interventions including adjuvant therapies with radiotherapy, systemic chemotherapy, and/or topical chemotherapy, an overall improvement on the 5-year survival rate in OSCC patients is still limited due to the aggressive local invasion and highly metastatic profile of OSCC [2,3,4,5]. Multiple cohort studies revealed that up to 40% of the patients experienced disease recurrence with increased tumor invasiveness within two years after completion of treatment [6,7,8]. Chemotherapy is the common choice of treatment of advanced OSCC for an overall improvement in the survival rate among patients. The development of an alternative treatment approach is crucial for improving the overall survival rate and the quality of life among patients
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