TY - JOUR
T1 - Synergistic induction of apoptosis by acyclic retinoid and interferon-β in human hepatocellular carcinoma cells
AU - Obora, Akihiro
AU - Shiratori, Yoshimune
AU - Okuno, Masataka
AU - Adachi, Seiji
AU - Takano, Yukihiko
AU - Matsushima-Nishiwaki, Rie
AU - Yasuda, Ichiro
AU - Yamada, Yasuhiro
AU - Akita, Kuniharu
AU - Sano, Tetsuro
AU - Shimada, Jun
AU - Kojima, Soichi
AU - Okano, Yukio
AU - Friedman, Scott L.
AU - Moriwaki, Hisataka
N1 - Funding Information:
Supported partly by Grants-in-Aid from the Ministry of Education, Science, Sports, Technology, and Culture of Japan (12670472 to M.O., 13670579 to S.K., 10557055 to H.M., and 13670135 to Y.O.) and a grant from the NIDDK (RO1DK37340 to S.L.F.).
PY - 2002/11/1
Y1 - 2002/11/1
N2 - Acyclic retinoid, a synthetic retinoid analog, as well as interferon alfa (IFN-α) and IFN-β 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 upregulation 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-β.
AB - Acyclic retinoid, a synthetic retinoid analog, as well as interferon alfa (IFN-α) and IFN-β 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 upregulation 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-β.
UR - http://www.scopus.com/inward/record.url?scp=0036829479&partnerID=8YFLogxK
U2 - 10.1053/jhep.2002.36369
DO - 10.1053/jhep.2002.36369
M3 - 学術論文
C2 - 12395321
AN - SCOPUS:0036829479
SN - 0270-9139
VL - 36
SP - 1115
EP - 1124
JO - Hepatology
JF - Hepatology
IS - 5 5 II
ER -