ATP Promotes Oral Squamous Cell Carcinoma Cell Invasion and Migration by Activating the PI3K/AKT Pathway via the P2Y2-Src-EGFR Axis

Qin Zhou; Shanshan Liu; Yuying Kou; Panpan Yang; Hongrui Liu; Tomoka Hasegawa; Rongjian Su; Guoxiong Zhu; Minqi Li

doi:10.1021/acsomega.2c03727

ATP Promotes Oral Squamous Cell Carcinoma Cell Invasion and Migration by Activating the PI3K/AKT Pathway via the P2Y2-Src-EGFR Axis

ACS Omega. 2022 Oct 26;7(44):39760-39771. doi: 10.1021/acsomega.2c03727. eCollection 2022 Nov 8.

Authors

Qin Zhou^{1

2}, Shanshan Liu^{1

2}, Yuying Kou^{1

2}, Panpan Yang^{1

2}, Hongrui Liu^{1

2}, Tomoka Hasegawa³, Rongjian Su⁴, Guoxiong Zhu⁵, Minqi Li^{1

2}

Affiliations

¹ Department of Bone Metabolism, School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University and Shandong Key Laboratory of Oral Tissue Regeneration and Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan 250100, China.
² Center of Osteoporosis and Bone Mineral Research, Shandong University, Jinan 250100, China.
³ Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine, Hokkaido University, Sapporo 060-0808, Japan.
⁴ College of Basic Medicine of Jinzhou Medical University, Cell Biology and Genetic Department of Jinzhou Medical University, Key Lab of Molecular and Cellular Biology of the Education Department of Liaoning Province, Life Science Institute of Jinzhou Medical University, Jinzhou 121001, China.
⁵ Department of Stomatology, No.960 Hospital of PLA, No. 25 Shifan Road, Jinan 250014, China.

Abstract

Oral cancer is one of the most common malignancies of the head and neck, and approximately 90% of oral cancers are oral squamous cell carcinomas (OSCCs). The purinergic P2Y2 receptor is upregulated in breast cancer, pancreatic cancer, colorectal cancer, and liver cancer, but its role in OSCC is still unclear. Here, we examined the effects of P2Y2 on the invasion and migration of oral cancer cells (SCC15 and CAL27). The BALB/c mouse model was used to observe the involvement of P2Y2 with tumors in vivo. P2Y2, Src, and EGFR are highly expressed in OSCC tissues and cell lines. Stimulation with ATP significantly enhanced cell invasion and migration in oral cancer cells, and enhanced the activity of Src and EGFR protein kinases, which is mediated by the PI3K/AKT signaling pathway. P2Y2 knockdown attenuated the above ATP-driven events in vitro and in vivo. The PI3K/AKT signaling pathway was blocked by Src or EGFR inhibitor. Extracellular ATP activates the PI3K/AKT pathway through the P2Y2-Src-EGFR axis to promote OSCC invasion and migration, and thus, P2Y2 may be a potential novel target for antimetastasis therapy.