title: PGE₂ targets squamous cell carcinoma cell with the activated epidermal growth factor receptor family for survival against 5-fluorouracil through NR4A2 induction.
abstract: We found a linear correlation between the Prostaglandin E(2) (PGE(2)) amount and the NR4A2 expression in oral squamous cell carcinoma (SCC) tissues through a statistical analysis among 41 clinical cases. In SCC cell lines, PGE(2) receptor (EP) ligation by exogenous PGE(2) promoted the NR4A2 expression in the cAMP/protein kinase A (PKA)-dependent manner. The process required a nature of SCC cell represented by constitutive activated epidermal growth factor receptor (EGFR) family. Targeted inactivation of the EGFRs interfered the PGE(2)-dependent NR4A2 expression. The PGE(2)-dependent NR4A2 induction is essential for the resistance to anti-cancer drug-induced apoptosis especially in SCC cells which showed constitutive EGFRs activity via autocrine epiregulin, a ligand for EGFRs. Conversely, SCC cells which lack epiregulin expression in their nature could gain the ability to promote the NR4A2 expression in response to PGE(2) and attain the resistance to anti-cancer drug-induced apoptosis under the existence of exogenous epiregulin. These findings suggest that susceptibility of SCC to anti-cancer drug could be compromised when PGE(2) was delivered in the microenvironment of SCC cells supported by constitutive EGFR family activities as their nature.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Division of Cervico-Gnathostomatology, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Shigeishi
authors.forename: Koichiro
authors.initials: K
authors.lastname: Higashikawa
authors.forename: Hiroko
authors.initials: H
authors.lastname: Hatano
authors.forename: Gaku
authors.initials: G
authors.lastname: Okui
authors.forename: Fumi
authors.initials: F
authors.lastname: Tanaka
authors.forename: Ta To
authors.initials: TT
authors.lastname: Tran
authors.forename: Andra
authors.initials: A
authors.lastname: Rizqiawan
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Ono
authors.forename: Kei
authors.initials: K
authors.lastname: Tobiume
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kamata
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D017931:DNA Primers; D015232:Dinoprostone / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism*; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D017931:DNA Primers; C539882:NR4A2 protein, human; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D066246:ErbB Receptors; D015232:Dinoprostone; D005472:Fluorouracil