title: Synergistic induction of apoptosis by acyclic retinoid and interferon-beta in human hepatocellular carcinoma cells.
abstract: Acyclic retinoid, a synthetic retinoid analog, as well as interferon alfa (IFN-alpha) and IFN-beta induce apoptosis in hepatocellular carcinoma (HCC) cells and are used clinically in the prevention of HCC. Here, we show that acyclic retinoid acts synergistically with IFNs in suppressing the growth and inducing apoptosis (as characterized by DNA fragmentation and chromatin condensation) in 5 human HCC cell lines (JHH7, HuH7, PLC/PRF/5, HLE, and HLF). This synergism was only observed when cells were pretreated with the acyclic retinoid, whereas natural retinoic acids (all-trans and 9-cis retinoic acid) were ineffective. This promotion may be due to up-regulation of type 1 IFN receptor (IFNR) expression by the retinoid. Accordingly, incubation with antitype 1 IFNR antibody abolished the synergy. Enhanced IFNR expression was accompanied by increased expression and DNA-binding activity of STAT1, an intracellular signal transducing molecule of IFNR, and increased induction of 2', 5'-oligoadenyl-5'-triphosphate synthetase, which is a target gene of STAT1. Acyclic retinoid did not have any effects on the growth of normal human hepatocytes (Hc) probably because of a lack of IFNR and STAT1 up-regulation. In conclusion, these results provide a rationale for combined biochemoprevention of HCC using acyclic retinoid and IFN-beta.
authors.affiliation: First Department of Internal Medicine and Department of Pathobiochemistry, Gifu University School of Medicine, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Obora
authors.forename: Yoshimune
authors.initials: Y
authors.lastname: Shiratori
authors.forename: Masataka
authors.initials: M
authors.lastname: Okuno
authors.forename: Seiji
authors.initials: S
authors.lastname: Adachi
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Takano
authors.forename: Rie
authors.initials: R
authors.lastname: Matsushima-Nishiwaki
authors.forename: Ichiro
authors.initials: I
authors.lastname: Yasuda
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamada
authors.forename: Kuniharu
authors.initials: K
authors.lastname: Akita
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Sano
authors.forename: Jun
authors.initials: J
authors.lastname: Shimada
authors.forename: Soichi
authors.initials: S
authors.lastname: Kojima
authors.forename: Yukio
authors.initials: Y
authors.lastname: Okano
authors.forename: Scott L
authors.initials: SL
authors.lastname: Friedman
authors.forename: Hisataka
authors.initials: H
authors.lastname: Moriwaki
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D016899:Interferon-beta / Q000494:pharmacology*; D008113:Liver Neoplasms; D012333:RNA, Messenger / Q000032:analysis; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D014212:Tretinoin; D016899:Interferon-beta; C034534:3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid