Modulation of PGE2-induced EP4 expression on snail signaling and the impact on epithelial-mesenchymal transition: significance of EP4 antagonism.
Copyright policy )Modulation of PGE2-induced EP4 expression on snail signaling and the impact on epithelial-mesenchymal transition: significance of EP4 antagonism.
Although significant accumulation of prostaglandin E(2) (PGE(2)) in the human prostate cancer tissues has been reported, there is lack of substantial evidence regarding the key role of PGE(2)-induced E-prostanoid-4 receptor (EP4) on Snail, a master regulator of epithelial mesenchymal transition (EMT). In this study, we investigated a novel connection between PGE(2)-induced EP4 and Snail (encodes DNA binding zinc finger protein that acts as transcriptional repressor) signaling in prostate cancer.To investigate the key role of serum PGE(2), EP4, p-Akt and Snail in prostate cancer progression, we used prostate-specific phosphatase and tensin homolog (PTEN)-knockout (PTEN-KO) mice of different age groups from 4 to 28 weeks. To determine the EP4-specific interaction with Snail in prostate cancer, we used cell-based assays, including siRNA knockdown, and treatment with EP4 antagonist.An interaction between EP4 with Snail was evident in prostate-specific PTEN-KO mice that showed an elevated level of PGE(2) in the serum and of EP4, p-Akt and Snail in the tissues. Prostate cancer cells transfected with EP4-siRNA and treatments with EP4 antagonist suggest a link between EP4, and Snail activation, potentially via p-Akt. Cells treated with EP4 antagonist exhibited a significant decrease in Snail, mesenchymal markers and cell migration, and cell cycle arrest with a gain in E-cadherin levels.Our findings provide key evidence that support there being a role of PGE(2)/EP4/p-Akt in Snail signaling and conferring cell survival advantage. Cancer progression via EMT can be reversed by an EP4 antagonist in this model of prostate cancer.
- New York University United States
Male, Mice, Knockout, Epithelial-Mesenchymal Transition, Prostatic Neoplasms, Dinoprostone, Immunoenzyme Techniques, Mice, Microscopy, Fluorescence, Cell Movement, Cell Line, Tumor, Disease Progression, Animals, Humans, Snail Family Transcription Factors, RNA, Small Interfering, Receptors, Prostaglandin E, EP4 Subtype, Cell Proliferation, Transcription Factors
Male, Mice, Knockout, Epithelial-Mesenchymal Transition, Prostatic Neoplasms, Dinoprostone, Immunoenzyme Techniques, Mice, Microscopy, Fluorescence, Cell Movement, Cell Line, Tumor, Disease Progression, Animals, Humans, Snail Family Transcription Factors, RNA, Small Interfering, Receptors, Prostaglandin E, EP4 Subtype, Cell Proliferation, Transcription Factors
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