title: Retinoic acid and its binding protein modulate apoptotic signals in hypoxic hepatocellular carcinoma cells.
abstract: Hypoxia induces survival signals in hepatocellular carcinoma (HCC). We attempted to find a hypoxia-induced signal that could be used for modulating HCC cell death. Cellular retinoic acid binding protein-II (CRABP-II) expression was significantly increased in hypoxic HCC cells. Treatment with retinoic acid (RA), a ligand for CRABP-II, induced HCC cell apoptosis more effectively in hypoxia than in normoxia, whereas hypoxia-induced CRABP-II expression attenuated RA-induced apoptosis. Inhibition of CRABP-II enhanced RA-induced apoptosis and sensitized RA-resistant HCC cells to RA cytotoxicity by attenuating p42/44 MAPK and Akt activation. Therefore, RA/CRABP-II signal modulation is therapeutically implicated in infiltrative HCCs exposed to hypoxia.
authors.affiliation: Department of Internal Medicine, Liver Research Institute, Seoul National University College of Medicine, Chongno-gu, Seoul, Republic of Korea.
authors.forename: Jeong-Hoon
authors.initials: JH
authors.lastname: Lee
authors.forename: Jung-Hwan
authors.initials: JH
authors.lastname: Yoon
authors.forename: Su Jong
authors.initials: SJ
authors.lastname: Yu
authors.forename: Goh Eun
authors.initials: GE
authors.lastname: Chung
authors.forename: Eun Uk
authors.initials: EU
authors.lastname: Jung
authors.forename: Hwi Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Bo Hyun
authors.initials: BH
authors.lastname: Kim
authors.forename: Dae Hee
authors.initials: DH
authors.lastname: Choi
authors.forename: Sun Jung
authors.initials: SJ
authors.lastname: Myung
authors.forename: Yoon Jun
authors.initials: YJ
authors.lastname: Kim
authors.forename: Chung Yong
authors.initials: CY
authors.lastname: Kim
authors.forename: Hyo-Suk
authors.initials: HS
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology*; D056811:Unfolded Protein Response
chemical_list: D000970:Antineoplastic Agents; D018168:Receptors, Retinoic Acid; C082928:retinoic acid binding protein II, cellular; D014212:Tretinoin