The EP4 antagonist, L-161,982, induces apoptosis, cell cycle arrest, and inhibits prostaglandin E2-induced proliferation in oral squamous carcinoma Tca8113 cells.
BACKGROUND
Recent studies suggest that cyclooxygenase 2 (COX-2) inhibitors may enhance the toxic effects of anticancer drugs on tumor cells, including oral squamous cell carcinoma (OSCC), but its long-term use can cause side effects such as stomach ulcers and myocardial infarction. Our aim was to investigate proliferative effects of a downstream product of COX-2, prostaglandin E2 (PGE2), in human oral squamous carcinoma cell line Tca8113 and explore the effects of PGE2 receptors, especially EP4 receptor, on the growth of Tca8113 cells.


METHODS
To evaluate the effects of PGE2 and EP receptors on Tca8113 cells, CCK8 assay, Western blotting, cell cycle analysis, and apoptosis assay were performed.


RESULTS
We found that the EP4 receptor agonist, PGE1-OH, could mimick PGE2 rescued the inhibitory effect of celecoxib and induced cell growth via ERK phosphorylation, and the EP4 receptor antagonist, L-161,982, completely blocked PGE2-stimulated ERK phosphorylation and proliferation of Tca8113 cells. Furthermore, L-161,982 may induce apoptosis and block cell cycle progression at s phase by upregulating Bax and p21 protein levels and by downregulating Bcl-2, CDK2, and cyclin A2 protein levels.


CONCLUSIONS
Our results indicate that EP4 receptor mediates PGE2-induced cell proliferation through ERK signaling, and inhibition of EP4 receptor may represent an alternative therapeutic strategy for the prevention and treatment of OSCC.
Department of Oral and Maxillofacial Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Xiaohui
X
Li
Department of Oral and Maxillofacial Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Bo
http://orcid.org/0000-0003-1952-7155
B
Yang
Department of Oral and Maxillofacial Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Guoxu
G
Han
Department of Oral and Maxillofacial Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Weizhong
W
Li
D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D015232:Dinoprostone / Q000037:antagonists & inhibitors*; D006801:Humans; D009062:Mouth Neoplasms / Q000473:pathology*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors*; D013876:Thiophenes / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C508711:L-161982; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013876:Thiophenes; D014230:Triazoles; D015232:Dinoprostone
L-161,982; cell growth; oral squamous cell carcinoma; prostaglandin E2