title: All-trans retinoic acid suppresses the adhering ability of ARPE-19 cells via mitogen-activated protein kinase and focal adhesion kinase.
abstract: This study investigated the signaling mechanism underlying the anti-adhesive effect of all-trans retinoic acid (ATRA) on retinal pigment epithelial ARPE-19 cells. Adhesion kinetics with or without ATRA treatment were profiled by adhesion assay. Surface coating with type IV collagen, fibronectin, laminin, but not type I collagen, significantly enhanced adhesion and spreading of ARPE-19 cells, while ATRA at subtoxic doses (ranging from 10-7to 10-6M) profoundly suppressed the extracellular matrix-enhanced adhesion ability. Cell attachment on FN activated PI3K/Akt and MAPK cascades, whereas ATRA pretreatment blunted the early phosphorylation of Akt and MAPK signaling mediators including p38 MAPK, JNK1/2, and ERK1/2. Mechanistically, signaling blockade with selective kinase inhibitors demonstrated that all MAPK pathways were involved in the anti-adhesive effect of ATRA, whereas the PI3K inhibitor treatment significantly potentiated the ATRA-suppressed RPE cell adhesion. Moreover, ATRA treatment did not affect intracellular F-actin distribution, but remarkably reduced focal adhesion kinase (FAK) expression and its nuclear localization during ARPE-19 cell attachment. In conclusion, ATRA suppresses the adhering ability of ARPE-19 cells at least in part through MAPK and FAK pathways. Signaling blockade with PI3K inhibitor could be regarded as an alternative modality for treating proliferative vitreoretinopathy.
authors.affiliation: Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Department of Ophthalmology, School of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
authors.forename: Yo-Chen
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Department of Ophthalmology, Chi Mei Medical Center, Tainan 71004, Taiwan; Graduate Institute of Medical Science, College of Health Science, Chang Jung Christian University, Tainan 71101, Taiwan.
authors.forename: Yuh-Shin
authors.initials: YS
authors.lastname: Chang
authors.affiliation: Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
authors.forename: Ming-Chu
authors.initials: MC
authors.lastname: Hsieh
authors.affiliation: Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
authors.forename: Horng-Jiun
authors.initials: HJ
authors.lastname: Wu
authors.affiliation: Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
authors.forename: Meng-Hsien
authors.initials: MH
authors.lastname: Wu
authors.affiliation: Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Lin
authors.affiliation: Department of Ophthalmology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. Electronic address: wuoph@kmu.edu.tw.
authors.forename: Wen-Chuan
authors.initials: WC
authors.lastname: Wu
authors.affiliation: Department of Medical Research, E-Da Hospital, I-Shou University, Kaohsiung 82445, Taiwan. Electronic address: danyhkao@gmail.com.
authors.forename: Ying-Hsien
authors.initials: YH
authors.lastname: Kao
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D014212:Tretinoin; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases
keywords: Extracellular matrix; Fibronectin; Focal adhesion kinase; Mitogen-activated protein kinase; PI3K inhibitor