title: Role of OATP2A1 in PGE(2) secretion from human colorectal cancer cells via exocytosis in response to oxidative stress.
abstract: Chronic inflammation induced by reactive oxygen species is associated with increased risk of developing colorectal cancer (CRC), and prostaglandin E2 (PGE2), which serves as a key mediator of inflammatory responses, plays an important role in CRC initiation and progression. Therefore, in the present study, we aimed to investigate the role of prostaglandin transporter OATP2A1/SLCO2A1 in the changes of PGE2 disposition in CRC cells in response to oxidative stress. H2O2 induced translocation of cytoplasmic OATP2A1 to plasma membranes in LoVo and COLO 320DM cells, but not in Caco-2 cells. The shift of subcellular OATP2A1 was abolished in the presence of anti-oxidant N-acetyl-L-cysteine or an inhibitor of protein kinase C, which evokes exocytosis. Exposure of LoVo cells to H2O2 caused an increase in the amount of extracellular PGE2 without changing the sum of intra- and extracellular PGE2. OATP2A1 knockdown decreased extracellular PGE2 in LoVo cells. In addition, extracellular PGE2 was significantly reduced by exocytosis inhibitor cytochalasin D, suggesting that H2O2-induced PGE2 release occurs in an exocytotic manner. Furthermore, mRNA expression of vascular endothelial growth factor (VEGF) was significantly reduced in LoVo cells by knockdown of OATP2A1. These results suggest that cytoplasmic OATP2A1 likely facilitates PGE2 loading into suitable intracellular compartment(s) for efficient exocytotic PGE2 release from CRC cells exposed to oxidative stress.
authors: Faculty of Pharmaceutical Science, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
authors: Taku
authors: T
authors: Kasai
authors: Faculty of Pharmaceutical Science, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
authors: Takeo
authors: T
authors: Nakanishi
authors: Faculty of Pharmaceutical Science, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
authors: Yasuhiro
authors: Y
authors: Ohno
authors: Faculty of Pharmaceutical Science, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
authors: Hiroaki
authors: H
authors: Shimada
authors: Faculty of Pharmaceutical Science, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
authors: Yoshinobu
authors: Y
authors: Nakamura
authors: Faculty of Pharmaceutical Science, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
authors: Hiroshi
authors: H
authors: Arakawa
authors: Faculty of Pharmaceutical Science, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. Electronic address: tamai@p.kanazawa-u.ac.jp.
authors: Ikumi
authors: I
authors: Tamai
mesh_terms: D018938:Caco-2 Cells; D015179:Colorectal Neoplasms / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism*; D005089:Exocytosis / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D027361:Organic Anion Transporters / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D027361:Organic Anion Transporters; D017382:Reactive Oxygen Species; C503526:SLCO2A1 protein, human; D042461:Vascular Endothelial Growth Factor A; D006861:Hydrogen Peroxide; D015232:Dinoprostone
keywords: Colorectal cancer; Exocytosis; OATP2A1; Prostaglandin E(2); Transporter