Synergistic induction of apoptosis by acyclic retinoid and interferon-beta in human hepatocellular carcinoma cells.
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.
Obora
Akihiro
A
First Department of Internal Medicine and Department of Pathobiochemistry, Gifu University School of Medicine, Japan.
Shiratori
Yoshimune
Y
Okuno
Masataka
M
Adachi
Seiji
S
Takano
Yukihiko
Y
Matsushima-Nishiwaki
Rie
R
Yasuda
Ichiro
I
Yamada
Yasuhiro
Y
Akita
Kuniharu
K
Sano
Tetsuro
T
Shimada
Jun
J
Kojima
Soichi
S
Okano
Yukio
Y
Friedman
Scott L
SL
Moriwaki
Hisataka
H
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
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