Open AccessProstaglandin E 2 receptor EP4 regulates cell migration through Orai1
Author(s) -
Osawa Kohei,
Umemura Masanari,
Nakakaji Rina,
Tanaka Ryo,
Islam Rafikul Md,
Nagasako Akane,
Fujita Takayuki,
Yokoyama Utako,
Koizumi Toshiyuki,
Mitsudo Kenji,
Ishikawa Yoshihiro
Publication year - 2020
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.14247
Subject(s) - microbiology and biotechnology , prostaglandin e2 receptor , cell migration , mapk/erk pathway , cancer research , gene knockdown , agonist , pi3k/akt/mtor pathway , protein kinase b , biology , signal transduction , receptor , chemistry , endocrinology , cell , cell culture , biochemistry , genetics
The EP4 prostanoid receptors are one of four receptor subtypes for prostaglandin E 2 (PGE 2 ). Therefore, EP4 may play an important role in cancer progression. However, little information is available regarding their function per se, including migration and the cellular signaling pathway of EP4 in oral cancer. First, we found that mRNA and protein expression of EP4 was abundantly expressed in human‐derived tongue squamous cell carcinoma cell lines HSC‐3 and OSC‐19. The EP4 agonist (ONO‐AE1‐437) significantly promoted cell migration in HSC‐3 cells. In contrast, knockdown of EP4 reduced cell migration. Furthermore, we confirmed that knockdown of EP4 suppressed metastasis of oral cancer cells in the lungs of mice in vivo. Therefore, we focused on the mechanism of migration/metastasis in EP4 signaling. Interestingly, EP4 agonist significantly induced intracellular Ca 2+ elevation not in only oral cancer cells but also in other cells, including normal cells. Furthermore, we found that EP4 activated PI3K and induced Ca 2+ influx through Orai1 without activation of store depletion and stromal interaction molecule 1 (STIM1). Immunoprecipitation showed that EP4 formed complexes with Orai1 and TRPC1, but not with STIM. Moreover, the EP4 agonist ONO‐AE1‐437 phosphorylated ERK and activated MMP‐2 and MMP‐9. Knockdown of Orai1 negated EP4 agonist‐induced ERK phosphorylation. Taken together, our data suggested that EP4 activated PI3K and then induced Ca 2+ influx from the extracellular space through Orai1, resulting in ERK phosphorylation and promoting cell migration. Migration is regulated by EP4/PI3K/Orai1 signaling in oral cancer.